Background The association between resting heart rate and ischemic stroke remains unclear. Aim To examine the association between resting heart rate and ischemic stroke. Methods A total of 24 730 participants (mean age: 64 ± 9·3 years; 59% women; 41% blacks) from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study who were free of stroke at the time of enrollment (2003–2007) were included in this analysis. Resting heart rate was determined from baseline electrocardiogram data. Heart rate was examined as a continuous variable per 10 bpm increase and also as a categorical variable using tertiles (<61 bpm, 61 to 70 bpm, and >70 bpm). First-time ischemic stroke events were identified during follow-up and adjudicated by physician review. Results Over a median follow-up of 7·6 years, a total of 646 ischemic strokes occurred. In a Cox regression model adjusted for socio-demographics, cardiovascular risk factors, and potential confounders, each 10 bpm increase in heart rate was associated with a 10% increase in the risk of ischemic stroke (hazard ratio = 1·10, 95% confidence interval = 1·02, 1·18). In the categorical model, an increased risk of ischemic stroke was observed for heart rates in the middle (hazard ratio = 1·29, 95% confidence interval = 1·06, 1·57) and upper (hazard ratio = 1·37, 95% confidence interval = 1·12, 1·67) tertiles compared with the lower tertile. The results were consistent when the analysis was stratified by age, gender, race, exercise habits, hypertension, and coronary heart disease. Conclusion In REGARDS, high resting heart rates were associated with an increased risk of ischemic stroke compared with low heart rates. Further research is needed to examine whether interventions aimed to reduce heart rate decrease stroke risk.