© 2015 American Academy of Pain Medicine. All rights reserved. Objective. Despite unknown risks, prescription opioid use (POU) for nonmalignant chronic pain has grown in the US over the last decade. The objective of this study was to examine associations between POU and coronary heart disease (CHD), stroke, and cardiovascular disease (CVD) death in a large cohort. Design, Setting, Subjects. POU was assessed in the prospective cohort study of 29,025 participants of the REasons for Geographic and Racial Differences in Stroke study, enrolled between 2003 and 2007 from the continental United States and followed through December 31, 2010. CHD, stroke, and CVD death were expert adjudicated outcome measures. Methods. Cox proportional hazards models adjusted for CVD risk factors were used. Results. Over a median (SD) of 5.2 (1.8) years of follow-up, 1,362 CHD events, 749 strokes, and 1,120 CVD death occurred (105, 55, and 104, respectively, in the 1,851 opioid users). POU was not associated with CHD (adjusted hazard ratio [aHR]) 1.03 [95% CI 0.83-1.26] or stroke (aHR 1.04 [95% CI 0.78-1.38]), but was associated with CVD death (aHR 1.24 [95% CI 1.00-1.53]) in the overall sample. In the sexstratified analyses, POU was associated with increased risk of CHD (aHR 1.38 [95% CI 1.05-1.82]) and CVD death (aHR 1.66 [95% CI 1.27-2.17]) among females but not males (aHR 0.70 [95% CI 0.50-0.97] for CHD and 0.78 [95% CI 0.54-1.11] for CVD death). Conclusion. Female but not male POU were at higher risk of CHD and CVD death. POU was not associated with stroke in overall or sex-stratified analyses.