Background/Objective: Motor vehicle collision (MVC)-related spinal cord injury (SCI) is the most prevalent etiology of SCI. Few studies have defined SCI risk factors. Vehicle mismatch occurs in 2-vehicle MVCs in which there are significant differences in vehicle weight, stiffness, and height. This study examined SCI risk and vehicle mismatch. Methods: A matched case-control study using the 1995 to 2003 National Automotive Sampling System (NASS). Study subjects were identified from 2-vehicle MVCs. Cases were occupants who had suffered a cervical, thoracic, or lumbar SCI. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Results: There were 101,682 cases of SCI matched to 805,091 controls. Occupants of passenger vehicles involved in MVCs with a light truck or van (LTV) were at increased risk for SCI (OR = 1.87, 95% CI = 1.07-3.24) and this risk was greatest for thoracic SCI (OR = 5.09, 95% CI = 2.33-11.13). In addition, occupants of LTVs involved in MVCs with passenger vehicles were at significant increased risk for cervical (OR = 1.39) and lumbar (OR = 2.65) SCI; and occupants of LTVs involved in MVCs with other LTVs were at increased risk of any SCI (OR = 2.02, 95% CI = 1.52-2.69). For these subjects, significant increased risks were seen for all spine regions: cervical (OR = 1.41), thoracic (OR = 2.86), and lumbar (OR = 2.38). Conclusions: The results of this study suggest that occupants of passenger vehicles are at increased SCI risk when involved in 2-vehicle MVCs with LTVs; and that occupants of LTVs are at increased SCI risk, regardless.