Background: Motor vehicle collisions (MVC) comprise a majority cause of referral to the emergency department (ED). A large proportion of MVC appear to be preventable, if more effective measures against driving after substance abuse can be implemented. Objective: This study was aimed to investigate the prevalence of substance abuse among drivers of MVC, following road traffic accidents (RTA). Materials and Methods: This case-control research was conducted from July to October 2007. One hundred MVC drivers admitted in the ED were included as the case group and 110 hospitalized patients, due to nontraumatic causes were used as controls. History of substances abused was obtained and urine samples were tested for opium in both groups. Finally the history and laboratory results of the groups were compared using SPSS 18. Results: Of the 100 patients in the case group, 39 (39%) were positive for substance abuse (100% males). On the other hand, 49 (44.5%) patients in the control group had positive history or laboratory findings of substance abuse (73.9% male). Opioids were the most common agent abused in both groups. There was no significant difference between two groups regarding the prevalence of substance abuse (P = 0.92). Conclusions: The prevalence of substance abuse is high among victims of road traffic injury but in equal proportion to the control group. Health education and counseling is needed to reduce substance abuse in the general population although it was not significantly related to the cause of RTA.