OBJECTIVE: To investigate sex and race differences in the association between fasting blood glucose (FBG) and risk of ischemic stroke (IS). METHODS: This prospective longitudinal cohort study included adults age ≥45 years at baseline in the Reasons for Geographic And Racial Differences in Stroke Study, followed for a median of 11.4 years. The exposure was baseline FBG (mg/dL); suspected IS events were ascertained by phone every 6 months and were physician-adjudicated. Cox proportional hazards were used to assess the adjusted sex/race-specific associations between FBG (by category and as a restricted cubic spline) and incident IS. RESULTS: Of 20,338 participants, mean age was 64.5 (SD 9.3) years, 38.7% were Black, 55.4% were women, 16.2% were using diabetes medications, and 954 IS events occurred. Compared to FBG <100, FBG ≥150 was associated with 59% higher hazards of IS (95% confidence interval [CI] 1.21-2.08) and 61% higher hazards of IS among those on diabetes medications (95% CI 1.12-2.31). The association between FBG and IS varied by race/sex (hazard ratio, FBG ≥150 vs FBG <100: White women 2.05 [95% CI 1.23-3.42], Black women 1.71 [95% CI 1.10-2.66], Black men 1.24 [95% CI 0.75-2.06], White men 1.46 [95% CI 0.93-2.28], pFBG×race/sex = 0.004). Analyses using FBG splines suggest that sex was the major contributor to differences by race/sex subgroups. CONCLUSIONS: Sex differences in the strength and shape of the association between FBG and IS are likely driving the significant differences in the association between FBG and IS across race/sex subgroups. These findings should be explored further and may inform tailored stroke prevention guidelines.