Objective: To estimate the risk of road traffic crash associated with prescription of antidepressants. Methods: Data from three French national databases were extracted and matched: the national health care insurance database, police reports, and the national police database of injurious crashes. A case-control analysis comparing 34,896 responsible versus 37,789 nonresponsible drivers was conducted. Case-crossover analysis was performed to investigate the acute effect of medicine exposure. Results: 72,685 drivers, identified by their national health care number, involved in an injurious crash in France over the July 2005 to May 2008 period, were included. 2,936 drivers (4.0%) were exposed to at least one antidepressant on the day of the crash. The results showed a significant association between the risk of being responsible for a crash and prescription of antidepressants (odds ratio (OR)=1.34, 95% confidence interval (CI) [1.22-1.47]). The case-crossover analysis showed no association with treatment prescription, but the risk of road traffic crash increased after an initiation of antidepressant treatment (OR=1.49 [1.24-1.79]) and after a change in antidepressant treatment (OR=1.32 [1.09-1.60]). Conclusions: Patients and prescribers should be warned about the risk of crash during periods of antidepressant medication and about particularly high vulnerability periods such as those when a treatment is initiated or modified.