Stroke incidence and mortality rates are higher in the southeastern region of the United States, which is called the "Stroke Belt." We compared the response to antihypertensive medication use in patients from different US regions.The short-term and 1-year efficacy of the antihypertensive medications hydrochlorothiazide, atenolol, diltiazem hydrochloride (sustained release), captopril, prazosin hydrochloride, and clonidine was compared by US region in a randomized controlled trial of 1,105 men with hypertension from 15 US Veterans Affairs medical centers.Compared with patients outside the Stroke Belt, patients inside the Stroke Belt achieved significantly lower treatment success rates of diastolic blood pressure control at 1 year with hydrochlorothiazide (63% vs 41%), atenolol (62% vs 46%), captopril (60% vs 30%), and clonidine (69% vs 43%); there were no differences in treatment success rates with diltiazem (70% vs 71%) or prazosin (54% vs 53%). When controlling for race, patients inside the Stroke Belt had significantly lower treatment success rates with hydrochlorothiazide (P = .003) and clonidine (P = .003), and the lower success rate with atenolol approached significance (P = .15). Regardless of region, blacks were less likely than whites to achieve treatment success with atenolol (P = .02) or prazosin (P = .03) and more likely with diltiazem (P = .05). There was a trend for blacks residing inside the Stroke Belt to have a lower treatment success rate than other race-region groups when treated with captopril (P = .07). Many regional and racial differences in diet, lifestyle, and other characteristics were observed. After adjustment for these characteristics by regression analysis, the effect of residing inside the Stroke Belt remained for captopril (P = .01) and clonidine (P = .01) and approached significance for hydrochlorothiazide (P = .10).Hypertension in patients residing inside the Stroke Belt responded less to the use of several antihypertensive medications and important differences were shown in a number of characteristics that may affect the control of blood pressure, compared with patients residing outside the Stroke Belt.