ABSTRACT Background: We assessed sex differences in stroke prevalence among individuals of midlife age (35 to 64 years) in the United States and determined factors predicting stroke. Methods: Data from 1999 to 2004 (n = 17,061) from the National Health and Nutrition Examination Survey, a nationally representative sample of US adults, were used to assess sex differences in stroke prevalence and to identify independent predictors of stroke occurrence among middle-aged individuals. Results: Women aged 45 to 54 years had significantly higher odds of having experienced a stroke vs men of the same age (odds ratio [OR] 2.39, 95% CI 1.32 to 4.32). No other significant midlife stroke differences between sexes were noted. A higher stroke trend was seen in 45- to 54-year-old women vs 35- to 44-year-old women (OR 2.13, 95% CI 0.95 to 4.80, p = 0.067), but no difference was seen in stroke rates in 55- to 64-year-old women vs 45- to 54-year-old women (OR 1.40, 95% CI 0.6912 to 2.8229, p = 0.352). Independent predictors of stroke in women aged 45 to 54 years were coronary artery disease (OR 12.790, 95% CI 1.901 to 86.063, p = 0.009) and waist circumference (OR 1.543, 95% CI 1.002 to 2.376, p = 0.049). Several vascular risk factors including systolic blood pressure and total cholesterol levels increased at higher rates among women compared with men in each successively older cohort from 35 to 64 years. Conclusions: A higher prevalence of stroke may exist among women aged 45 to 54 years compared with similarly aged men. This potential disparity could be due in part to inadequate stroke risk factor modification in women and is deserving of further study.