Background Patients with Restless Legs Syndrome (RLS) have been recently reported to have a higher risk of stroke when compared to non-RLS patients, but the difference appears to be related to the duration of RLS. We hypothesize that diabetes mellitus, a condition that accelerates cardiovascular diseases, may enhance the risk of stroke more in RLS than in non-RLS patients. Methods and Results Patients diagnosed with RLS based on the International Restless Legs Syndrome Study Group criteria from a community-based sleep study center were compared to a 1:2 propensity matched non-RLS group. The association of diabetes and stroke in RLS and non-RLS patients in men and women were performed using Chi-Square and Cochran-Mantel-Haenszel Tests. Results Stroke was diagnosed in 29 out of 385 (7.5%) patients with RLS (mean age 55.1±0.7 years, 45% female) which was significantly higher than 32 out of 770 (4.2%; p=0.02) patients without RLS (mean age 54±0.5 years, 46% females). The presence of diabetes in the RLS group was associated with a 3 fold increased risk of stroke (OR 2.96, 95% Confidence Interval 1.05-8.37, p=0.03) compared to a 1.1 fold increased risk in non-RLS patients (OR: 1.08, 95% CI 0.44-2.65; p=0.87). This was significantly higher in female diabetics with RLS (18.2%) than in male diabetics (7.0%, p=0.03) or nondiabetics (5.7% in females vs 3.9% in males, p=0.52). Predictors of stroke in patients with RLS were the presence of hypertension, diabetes and female sex. Hypertension, diabetes and atrial fibrillation were predictors of stroke in non-RLS patients. Conclusions Gender differences exist in the risk of stroke in RLS patients with a 3.0 fold higher risk of stroke in diabetic women compared to diabetic men. In non-RLS patients, no significant difference in risk of stroke was found between women and men. Mechanisms underlying increased risk of stroke in RLS patients need to be defined and whether better diabetes control help reduce the stroke risk in RLS patients needs to be further investigated