© 2014 National Stroke Association. Background Preliminary evidence suggests sleep medications are associated with risk of vascular events; however, the long-term vascular consequences are understudied. This study investigated the relation between sleep medication use and incident stroke.Methods Within the REasons for Geographic And Racial Differences in Stroke study, 21,678 black participants and white participants (<45 years) with no history of stroke were studied. Participants were recruited from 2003 to 2007. From 2008 to 2010, participants self reported their prescription and over-the-counter sleep medication use over the past month. Suspected stroke events were identified by telephone contact at 6-month intervals and associated medical records were retrieved and physician-adjudicated. Proportional hazards analysis was used to estimate hazard ratios for incident stroke associated with sleep medication use (0, 1-14, and 15+ days per month) controlling for sociodemographics, stroke risk factors, mental health symptoms, and sleep apnea risk.Results At the sleep assessment, 9.6% of the sample used prescription sleep medication and 11.1% used over-the-counter sleep aids. Over an average follow-up of 3.3 ± 1.0 years, 297 stroke events occurred. Over-the-counter sleep medication use was associated with increased risk of incident stroke in a frequency-response relationship (P =.014), with a 46% increased risk for 1-14 days of use per month (hazards ratio [HR] = 1.46; 95% confidence interval [CI],.99-2.15) and a 65% increased risk for 15+ days (HR = 1.65; 95% CI,.96-2.85). There was no significant association with prescription sleep medications (P =.80).Conclusions Over-the-counter sleep medication use may independently increase the risk of stroke beyond other risk factors in middle-aged to older individuals with no history of stroke.