Background: This study sought to describe variations in the risk of motor vehicle collision (MVC) injury and death by occupant body mass index (BMI) class and vehicle type. We hypothesized that the relationship between BMI and the risk of MVC injury or mortality would be modified by vehicle type. Methods: This is a retrospective cohort study of occupants involved in MVCs using data from the Crash Injury Research and Engineering Network and the National Automotive Sampling System Crashworthiness Data System. Occupants were grouped based on vehicle body style (passenger car, sport utility vehicle, or light truck) and vehicle size (compact or normal, corresponding to below- or above-average curb weight). The relationship between occupant BMI class (underweight, normal weight, overweight, or obese) and risk of injury or mortality was examined for each vehicle type. Odds ratios (ORs) adjusted for various occupant and collision characteristics were estimated. Results: Of an estimated 44 million occupants of MVCs sampled from 2000 to 2009, 37.1% sustained an injury. We limited our analysis to injuries achieving an Abbreviated Injury Scale (AIS) score of 2 or more severe, totaling 17 million injuries. Occupants differed substantially in terms of demographic and collision characteristics. After adjustment for confounding factors, we found that obesity was a risk factor for mortality caused by MVC (OR, 1.6; 95% confidence interval [CI], 1.2-2.0). When stratified by vehicle type, we found that obesity was a risk factor for mortality in larger vehicles, including any-sized light trucks (OR, 2.1; 95% CI, 1.3-3.5), normal-sized passenger cars (OR, 1.6; 95% CI, 1.1-2.3), and normal-sized sports utility vehicles or vans (OR, 2.0; 95% CI, 1.0-3.8). Being overweight was a risk factor in any-sized light trucks (OR, 1.5; 95% CI, 1.1-2.1). Conclusion: We identified a significant interaction between occupant BMI class and vehicle type in terms of MVC-related mortality risk. Both factors should be taken into account when considering occupant safety, and additional study is needed to determine underlying causes of the observed relationships. LEVEL OF EVIDENCE: Epidemiologic study, level III. © 2014 2014 Lippincott Williams & Wilkins.