IMPORTANCE: Race-specific and sex-specific stroke risk varies across the lifespan, yet few reports describe sex differences in stroke risk separately in black individuals and white individuals. OBJECTIVE: To examine incidence and risk factors for ischemic stroke by sex for black and white individuals. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study included participants 45 years and older who were stroke-free from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort, enrolled from the continental United States 2003 through 2007 with follow-up through October 2016. Data were analyzed from March 2018 to September 2018. EXPOSURES: Sex and race. MAIN OUTCOMES AND MEASURES: Physician-adjudicated incident ischemic stroke, self-reported race/ethnicity, and measured and self-reported risk factors. RESULTS: A total of 25 789 participants (14 170 women 54.9%; 10 301 black individuals 39.9%) were included. Over 222 120 person-years of follow-up, 939 ischemic strokes occurred: 159 (16.9%) in black men, 326 in white men (34.7%), 217 in black women (23.1%), and 237 in white women (25.2%). Between 45 and 64 years of age, white women had 32% lower stroke risk than white men (incidence rate ratio IRR, 0.68 95% CI, 0.49-0.94), and black women had a 28% lower risk than black men (IRR, 0.72 95% CI, 0.52-0.99). Lower stroke risk in women than men persisted at age 65 through 74 years in white individuals (IRR, 0.71 95% CI, 0.55-0.94) but not in black individuals (IRR, 0.94 95% CI, 0.68-1.30); however, the race-sex interaction was not significant. At 75 years and older, there was no sex difference in stroke risk for either race. For white individuals, associations of systolic blood pressure (women: hazard ratio HR, 1.13 95% CI, 1.05-1.22; men: 1.04 95% CI, 0.97-1.11; P = .099), diabetes (women: HR, 1.84 95% CI, 1.35-2.52; men: 1.13 95% CI, 0.86-1.49; P = .02), and heart disease (women: HR, 1.76 95% CI, 1.30-2.39; men, 1.26 95% CI, 0.99-1.60; P = .09) with stroke risk were larger for women than men, while antihypertensive medication use had a smaller association in women than men (women: HR, 1.17 95% CI, 0.89-1.54; men: 1.61 95% CI, 1.29-2.03; P = .08). In black individuals, there was no evidence of a sex difference for any risk factors. CONCLUSIONS AND RELEVANCE: For both races, at age 45 through 64 years, women were at lower stroke risk than men, and there was no sex difference at 75 years or older; however, the sex difference pattern may differ by race from age 65 through 74 years. The association of risk factors on stroke risk differed by race-sex groups. While the need for primordial prevention, optimal management, and control of risk factors is universal across all age, racial/ethnic, and sex groups, some demographic subgroups may require earlier and more aggressive strategies.