There has been increasing concern regarding the role of prescription drug use in the causation of traffic crashes. The goal of this research is to describe the prevalence of prescription drug use among injured trauma patients and determine the association between classes of drugs and crash culpability, a surrogate measure of crash risk. Methods: Patient records, including chronic medication usage, for all drivers admitted to a trauma center following a traffic collision in 2008 (N=1,558) were linked with police crash reports to determine crash culpability. Multivariable analyses explored the association between medication use and crash culpability among non-drinking drivers. Adjusted odds ratios and 95% confidence intervals were compared among drivers who were and were not using central nervous system (CNS)-acting medications (single and multiple). Results: 61.5% of all drivers were using any medications and usage increased with age, as did numbers of prescriptions per driver. Logistic regression analyses revealed that drivers who used CNS medications had an increased risk of culpability; those on more than one such medication had a crude (unadjusted) odds ratio of 2.16 for having caused the crash. Among drivers less than 45 years old, CNS medications did not significantly increase the risk of crash culpability. However, among drivers aged 45 or greater, the odds ratios for one, two, or 2+ CNS medications vs. none increased dramatically from 1.89 to 4.23 to 7.99, respectively. Conclusions: These results suggest that special attention should be given to older drivers (45+) using two or more CNS-acting agents.