Background: Diaphragmatic rupture (DR) remains a diagnostic challenge because of the lack of an accurate test demonstrating the injury. Our purpose was to identify motor vehicle collision (MVC) characteristics and patient injuries that collectively could identify the presence of a DR. Methods: The National Automotive Sampling System was used to identify occupants involved in MVCs from 1995 to 1999 who sustained abdominal (Abbreviated Injury Scale score ≥ 2) and/or thoracic injuries (Abbreviated Injury Scale score ≥ 2). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to quantify the association between patient injuries, vehicle collision characteristics, and DR. Sensitivity and specificity were also calculated to determine the ability of organ injury and MVC characteristics to correctly classify patients with and without DR. Results: Overall, occupants sustaining a DR had a significantly higher delta-V (ΔV) (49.8 kilometers per hour [kph] vs. 33.8 kph, p < 0.0001) and a greater degree of occupant compartment intrusion (70.6 cm vs. 48.3 cm, p < 0.0001). Specific abdominal and thoracic organ injuries were associated with DR, including thoracic aortic tears (OR, 5.2; 95% CI, 2.2-12.5), splenic injury (OR, 8.4; 95% CI, 3.9-17.8), pelvic fractures (OR, 4.7; 95% CI, 2.7-8.0), and hepatic injuries (OR, 4.2; 95% CI, 1.7-10.6). Combining frontal or near-side lateral occupant compartment intrusion ≥ 30 cm or ΔV ≥ 40 kph with specific organ injuries generated a sensitivity for indicating the likelihood of diaphragm injury ranging from 68% to 89%. Patients with any of the following characteristics had a sensitivity for detecting DR of 91 %: splenic injury, pelvic fracture, ΔV ≥ 40 kph, or occupant compartment intrusion from any direction ≥ 30 cm. Conclusion: Specific MVC characteristics combined with patient injuries have been identified that are highly suggestive of DR. For this subpopulation, additional invasive procedures including exploratory laparotomy, laparoscopy, or thoracoscopy may be warranted to exclude DR.