The authors examined the association between prescribed medications and fatal motor vehicle crashes (MVCs) in an active duty military population between 2002 and 2006. Using a case–control design, MVC deaths were ascertained using a military mortality registry, and an integrated health system database provided information on health system eligibility, pharmacy transactions, and medical encounters. Cases and controls were matched on comparable observation time outside periods of deployment. Among selected categories, only one, antidepressant medications, was an independent predictor of fatal MVC (odds ratio, 3.19; 95% confidence interval, 1.01–10.07). Male gender, Black race, enlisted rank, service branch (Navy and Marine Corps), and selected co-morbidities were also independent predictors. Unexpectedly, the odds of younger age quartiles (<27 years) and history of deployment were reduced for MVC cases. Although results need to be considered in the context of data limitations, the association between prescribed antidepressants and fatal MVC may reflect unmeasured co-morbidities, such as combined effects of prescribed and over-the-counter medications and/or alcohol or other substance abuse. Younger individuals, representing new military accessions in training or returning from deployment with serious injuries, may have fewer opportunities to operate vehicles, or targeted efforts to reduce MVC following deployment may be showing a positive effect.