Cardiac effects of hypertension include increased left ventricular (LV) mass and LV hypertrophy, as well as increased left atrial size, a predictor of stroke and atrial fibrillation. Although literature on reduction of LV mass with antihypertensive therapy is extensive, little information is available on effects of treatment on left atrial size. Patients with mild to moderate hypertension (diastolic blood pressure 95 to 109 mm Hg) were randomly allocated to treatment with atenolol, captopril, clonidine, diltiazem, hydrochlorothiazide, or prazosin in a double-masked trial. Two-dimensional targeted M-mode echocardiography was used to assess left atrial size and LV mass at baseline, 8 weeks, and 1 and 2 years. Longitudinal analysis examined changes in left atrial size from the baseline study, statistically adjusting for age, race, pretreatment left atrial size and LV mass, and serial measurements of systolic blood pressure, body weight, urinary sodium excretion, and physical activity score. Without adjustment for covariates, only hydrochlorothiazide was associated with decreases in left atrial size from baseline at 8 weeks (-1.0 +/- 5.2 mm; P=0.052), 1 year (-2.0 +/- 5.1 mm; P=0.02), and 2 years (4.6+/-7.2 mm; P=0.002). After adjustment for effects of covariates, patients with normal left atrial size had greater reduction (-3.3 mm) in left atrial size at 2 years with hydrochlorothiazide than with any other drug. For patients with left atrial enlargement, left atrial size decreased significantly with hydrochlorothiazide, atenolol, clonidine, and diltiazem at 1 year and with all treatments at 2 years. However, reduction at 2 years was greater with hydrochlorothiazide than with captopril or prazosin. Antihypertensive drugs differ in their effects on left atrial size. Hydrochlorothiazide was associated with greater overall reduction of left atrial size than other drugs effective for the treatment of hypertension. Reduction of left atrial size with therapy is in part independent of factors known to influence left atrial size, including LV mass and reduction of LV mass with treatment. The clinical benefit of reducing left atrial size with antihypertensive treatment remains to be determined.