© 2019 by the American Diabetes Association. Objective: Given temporal changes in diabetes prevalence and stroke incidence, this study investigated age, race, and sex differences in the diabetes-stroke association in a contemporary prospective cohort, the REasons for Geographic and Racial Differences in Stroke (REGARDS) Study. Research Design and Methods: We included 23,002 non-Hispanic black and white U.S. adults aged ≥45 years without prevalent stroke at baseline (2003-2007). Diabetes was defined as fasting glucose ≥126 mg/dL, random glucose ≥200 mg/dL, or use of glucose-lowering medication. Incident stroke events were expert adjudicated and available through September 2017. Results: The prevalence of diabetes was 19.1% at baseline. During follow-up, 1,018 stroke events occurred. Among adults aged <65 years, comparing those with diabetes to those without diabetes, the risk of stroke was increased for white women (hazard ratio [HR] 3.72 [95% CI 2.10-6.57]), black women (HR 1.88 [95% CI 1.22-2.90]), and white men (HR 2.01 [95% CI 1.27-3.27]) but not black men (HR 1.27 [95% CI 0.77- 2.10]) after multivariable adjustment. Among those aged ≥65 years, diabetes increased the risk of stroke for white women and black men, but not black women (HR 1.05 [95% CI 0.74-1.48]) or white men (HR 0.86 [95% CI 0.62-1.21]). Conclusions: In this contemporary cohort, the diabetes-stroke association varied by age, race, and sex together, with a more pronounced effect observed among adults aged <65 years. With the recent increase in the burden of diabetes complications at younger ages in the U.S., additional efforts are needed earlier in life for stroke prevention among adults with diabetes.