The relationship between restless legs syndrome (RLS) and cardiovascular disease remains enigmatic in the general population, and its prognostic value in patients with coronary artery disease (CAD) is unknown. In this study, the frequency of RLS-like symptoms was assessed using a validated instrument in 3,266 patients undergoing cardiac catheterization (mean age 64 years, 62% male, 23% Black, and 74% with obstructive CAD). Patients were followed for primary end points of cardiovascular death or incident myocardial infarction. Fine and Gray hazard models explored the association between RLS and incident events after adjustment for demographic and clinical risk factors. In the total cohort, 29% of patients reported mild (rare or sometimes) symptoms, and 15% of patients had moderate/severe (often to almost always) symptoms of RLS. Female sex (odds ratio [OR] 2.11, 95% confidence interval (CI), 1.68 to 2.57), body mass index (OR 1.12 per 5 kg/m², 95% CI, 1.04 to 1.22), diabetes (OR 1.43, 95%,1.15 to 1.79), and β-blocker use (OR 1.35, 95% CI, 1.07 to 1.72) were independently associated with moderate/severe symptoms of RLS compared with no symptoms. Over a 5-year follow-up period, 991 patients suffered an adverse event. Compared with those with no symptoms, patients with moderate/severe RLS had significantly higher risk of the primary end point (hazard ratio [HR] = 1.33, 95%),CI 1.01 to 1.76) after adjustment for demographic and clinical risk factors. The association was more significant in men than women, HR 1.98, 95% CI, 1.41 to 2.78 versus HR 0.99 (,95% CI, 0.64 to 1.52, p interaction= 0.013. In conclusion, among men with CAD, moderate-to-severe symptoms of RLS are associated with significantly higher risk of adverse cardiovascular outcomes, independent of traditional risk factors.