To compare risks of unsafe driving in patients with medical conditions. This large population-based study included all patients who were referred for a fitness-to-drive evaluation at an official driving evaluation center in 2013 and 2014. Risks of unsafe driving included physician's fitness-to-drive recommendation, comprehensive fitness-to-drive decision, motor vehicle crash history, and traffic violation history. A total of 6584 patients were included in the study. Risks of unsafe driving were significantly different across medical conditions (P<.001 for all outcome measures). Patients with neurological conditions comprised the majority of the database (4837; 74%), but were not at the highest risk for unsafe driving. Patients with psychiatric conditions or substance abuse did worse on most driving safety outcomes, despite their low representation in the total sample (359 [6%] and 46 [1%], respectively). The risk of unsafe driving varied greatly across medical conditions. Sensitization campaigns, education, and medical guidelines for physicians and driver licensing authorities are warranted to identify patients at risk, especially for those with psychiatric conditions and substance abuse problems. Copyright © 2017 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.