We examined the contribution of stroke risk factors to midlife (age 45-59 years) Mexican American and non-Hispanic White ischemic stroke (IS) rate disparities from 2000 to 2010. Incident IS cases (n=707) and risk factors were identified from the Brain Attack Surveillance in Corpus Christi Project, Nueces County, TX (2000-2010). US Census data (2000-2010) were used to estimate the population at-risk for IS, and the Behavioral Risk Factor Surveillance System (2000-2010) was used to estimate risk factor prevalence in the stroke-free population. Poisson regression models combined IS counts (numerator) and population at-risk counts (denominator) classified by ethnicity and risk factor status to estimate unadjusted and risk factor-adjusted associations between ethnicity and IS rates. Separate models were run for each risk factor and extended to include an interaction term between ethnicity and risk factor. The crude rate ratio (RR) for ethnicity (Mexican American versus non-Hispanic White) was 2.01 (95% confidence interval [CI], 1.71-2.36) and was attenuated in models that adjusted for diabetes mellitus (RR: 1.50; 95% CI, 1.26-1.78) and hypertension (RR: 1.84; 95% CI, 1.50-2.26). In addition, diabetes mellitus had a stronger association with IS rates among Mexican Americans (RR: 6.42; 95% CI, 5.31-7.76) compared with non-Hispanic Whites (RR: 4.07; 95% CI, 3.68-4.51). The higher prevalence of diabetes mellitus and hypertension and stronger association of diabetes mellitus with IS among midlife Mexican Americans likely contribute to persistent midlife ethnic stroke disparities.