diff --git a/rfdiffusion/inference/model_runners.py b/rfdiffusion/inference/model_runners.py
index 2bd0d530..0de18784 100644
--- a/rfdiffusion/inference/model_runners.py
+++ b/rfdiffusion/inference/model_runners.py
@@ -17,6 +17,13 @@
 import string
 
 from rfdiffusion.model_input_logger import pickle_function_call
+from rfdiffusion.validation import (
+    validate_pdb_path,
+    validate_checkpoint_path,
+    validate_contig_string,
+    validate_hotspot_res,
+    validate_diffuser_config,
+)
 import sys
 
 SCRIPT_DIR = os.path.dirname(os.path.realpath(__file__))
@@ -112,6 +119,14 @@ def initialize(self, conf: DictConfig) -> None:
         ), "trb_save_ckpt_path is not the place to specify an input model. Specify in inference.ckpt_override_path"
         self._conf["inference"]["trb_save_ckpt_path"] = self.ckpt_path
 
+        # Validate inputs early, before GPU allocation and model loading
+        validate_checkpoint_path(self.ckpt_path)
+        if conf.inference.input_pdb is not None:
+            validate_pdb_path(conf.inference.input_pdb)
+        validate_diffuser_config(conf.diffuser)
+        if conf.ppi.hotspot_res is not None:
+            validate_hotspot_res(conf.ppi.hotspot_res)
+
         #######################
         ### Assemble Config ###
         #######################
@@ -313,6 +328,10 @@ def sample_init(self, return_forward_trajectory=False):
         ### Generate specific contig ###
         ################################
 
+        # Validate contig string before parsing
+        if self.contig_conf.contigs is not None:
+            validate_contig_string(self.contig_conf.contigs)
+
         # Generate a specific contig from the range of possibilities specified at input
 
         self.contig_map = self.construct_contig(self.target_feats)
diff --git a/rfdiffusion/validation.py b/rfdiffusion/validation.py
new file mode 100644
index 00000000..34def603
--- /dev/null
+++ b/rfdiffusion/validation.py
@@ -0,0 +1,184 @@
+"""Input validation for RFdiffusion inference.
+
+Catches common configuration and input errors early, before model loading
+and GPU allocation, so users get clear error messages instead of cryptic
+tensor shape mismatches deep in the forward pass.
+"""
+
+import os
+import re
+import logging
+
+logger = logging.getLogger(__name__)
+
+
+class ValidationError(ValueError):
+    """Raised when input validation fails with a user-friendly message."""
+    pass
+
+
+def validate_pdb_path(pdb_path: str) -> None:
+    """Validate that a PDB file exists and contains parseable ATOM records.
+
+    Args:
+        pdb_path: Path to input PDB file.
+
+    Raises:
+        ValidationError: If file doesn't exist or has no ATOM records.
+    """
+    if not os.path.isfile(pdb_path):
+        raise ValidationError(
+            f"Input PDB file not found: {pdb_path}"
+        )
+
+    has_atoms = False
+    with open(pdb_path, "r") as f:
+        for line in f:
+            if line.startswith(("ATOM", "HETATM")) and len(line) >= 54:
+                has_atoms = True
+                try:
+                    float(line[30:38])
+                    float(line[38:46])
+                    float(line[46:54])
+                except ValueError:
+                    raise ValidationError(
+                        f"Invalid coordinates in PDB line: {line.rstrip()}"
+                    )
+                break
+
+    if not has_atoms:
+        raise ValidationError(
+            f"PDB file contains no ATOM/HETATM records: {pdb_path}"
+        )
+
+
+def validate_contig_string(contigs: list) -> None:
+    """Validate contig string syntax before parsing.
+
+    Args:
+        contigs: List of contig specification strings.
+
+    Raises:
+        ValidationError: If contig syntax is invalid.
+    """
+    if not contigs or not isinstance(contigs, (list, tuple)):
+        raise ValidationError(
+            "contigs must be a non-empty list of strings. "
+            "Example: ['10-20/A5-50/0 30-40']"
+        )
+
+    contig_str = contigs[0]
+    if not isinstance(contig_str, str) or not contig_str.strip():
+        raise ValidationError(
+            f"Contig string must be a non-empty string, got: {contig_str!r}"
+        )
+
+    for segment in contig_str.strip().split():
+        for part in segment.split("/"):
+            part = part.strip()
+            if not part:
+                continue
+            # Chain break marker
+            if part == "0":
+                continue
+            # Numeric range: "10-20" or "10"
+            if part[0].isdigit():
+                if "-" in part:
+                    pieces = part.split("-")
+                    if len(pieces) != 2:
+                        raise ValidationError(
+                            f"Invalid contig range format: '{part}'. "
+                            f"Expected 'N-M' (e.g., '10-20')."
+                        )
+                    try:
+                        lo, hi = int(pieces[0]), int(pieces[1])
+                    except ValueError:
+                        raise ValidationError(
+                            f"Non-integer values in contig range: '{part}'"
+                        )
+                    if lo < 0 or hi < 0:
+                        raise ValidationError(
+                            f"Negative value in contig range: '{part}'"
+                        )
+                    if lo > hi:
+                        raise ValidationError(
+                            f"Invalid contig range: '{part}' (start > end)"
+                        )
+            # Chain-residue range: "A5-50" or "A5"
+            elif part[0].isalpha():
+                if not re.match(r"^[A-Za-z]\d+(-\d+)?$", part):
+                    logger.warning(f"Unusual contig segment: '{part}'")
+
+
+def validate_checkpoint_path(ckpt_path: str) -> None:
+    """Validate that a model checkpoint file exists.
+
+    Args:
+        ckpt_path: Path to model checkpoint.
+
+    Raises:
+        ValidationError: If checkpoint file doesn't exist.
+    """
+    if not os.path.isfile(ckpt_path):
+        raise ValidationError(
+            f"Model checkpoint not found: {ckpt_path}. "
+            f"Please download models following the README instructions."
+        )
+
+
+def validate_hotspot_res(hotspot_res: list) -> None:
+    """Validate hotspot residue format (e.g., ['A50', 'B123']).
+
+    Args:
+        hotspot_res: List of hotspot residue strings.
+
+    Raises:
+        ValidationError: If format is invalid.
+    """
+    if hotspot_res is None:
+        return
+
+    for res in hotspot_res:
+        if not isinstance(res, str) or len(res) < 2:
+            raise ValidationError(
+                f"Invalid hotspot residue format: {res!r}. "
+                f"Expected format like 'A50' (chain letter + residue number)."
+            )
+        if not res[0].isalpha():
+            raise ValidationError(
+                f"Hotspot residue must start with a chain letter: {res!r}"
+            )
+        try:
+            int(res[1:])
+        except ValueError:
+            raise ValidationError(
+                f"Hotspot residue number must be an integer: {res!r}"
+            )
+
+
+def validate_diffuser_config(diffuser_conf) -> None:
+    """Validate diffuser configuration parameters.
+
+    Args:
+        diffuser_conf: Diffuser configuration object.
+
+    Raises:
+        ValidationError: If parameters are out of valid range.
+    """
+    T = getattr(diffuser_conf, "T", None)
+    partial_T = getattr(diffuser_conf, "partial_T", None)
+
+    if T is not None and T < 1:
+        raise ValidationError(
+            f"diffuser.T must be >= 1, got {T}"
+        )
+    if partial_T is not None:
+        if partial_T < 1:
+            raise ValidationError(
+                f"diffuser.partial_T must be >= 1, got {partial_T}"
+            )
+        if T is not None and partial_T > T:
+            raise ValidationError(
+                f"diffuser.partial_T ({partial_T}) cannot exceed "
+                f"diffuser.T ({T})"
+            )