© 2019 American Heart Association, Inc. Little is known about whether the relationship between hypertension and ischemic stroke differs by sex. We examined sex differences in the association between hypertension severity and treatment and ischemic stroke risk. We used a longitudinal cohort study in the continental United States, with oversampling of black individuals and those living in the stroke belt. We included 26 461 participants recruited from 2003 to 2007 without prevalent stroke at baseline. The main outcome was incident ischemic stroke ascertained by telephone surveillance (with physician adjudication for suspected events). Proportional hazards regression was used to assess the sex-specific association between systolic blood pressure and stroke and between classes of antihypertensive medications and stroke after adjustment for age, race, sex, and age-by-race and sex-by-treatment interaction terms. A priori, P<0.10 was considered significant for interactions. Among participants (55.4% women, 40.2% black), there were 1084 confirmed ischemic stroke events. In the adjusted model, the risk of stroke per each level of hypertension (referent/systolic blood pressure <120 mm Hg/120-129 mm Hg/130-139 mm Hg/>140 mm Hg) was higher in women (hazard ratio, 1.25; 95% CI, 1.16-1.34) than men (hazard ratio, 1.14; 95% CI, 1.05-1.23; sex-systolic blood pressure interaction term, P=0.09). Compared with no medications, with each additional class of medications, stroke risk increased by 23% (hazard ratio, 1.23; 95% CI, 1.14-1.33) for women and 21% (hazard ratio, 1.21; 95% CI, 1.12-1.31) for men (P=0.79). Further work on the biological mechanisms for sex differences in stroke risk associated with hypertension severity and a need for sex-specific clinical guidelines may be warranted.