This multicenter, factorial-design trial assessed the safety and additive antihypertensive efficacy of a slow-release (SR) formulation of diltiazem hydrochloride given alone or in combination with hydrochlorothiazide for treatment of mild to moderate hypertension. After a 4- to 6-week placebo run-in period, 297 qualifying patients were randomized to receive placebo, 1 of 4 doses of diltiazem SR monotherapy, 1 of 3 doses of hydrochlorothiazide monotherapy, or 1 of 12 possible combinations of diltiazem SR and hydrochlorothiazide for 6 weeks. A dose-related reduction in blood pressure was demonstrated for each drug as monotherapy and for the two drugs in combination. Absolute blood pressures of patients who received combination therapy were lower by an overall mean of 3.0 mm Hg diastolic and 8.0 mm Hg systolic vs diltiazem SR used alone and 3.5 mm Hg diastolic and 4.0 mm Hg systolic vs hydrochlorothiazide used alone. At the largest doses used, 50% of patients achieved goal blood pressure while taking hydrochlorothiazide, 57% while taking diltiazem SR, and 75% while taking combination therapy. Combination therapy was well tolerated. This trial clearly demonstrates that diltiazem SR and hydrochlorothiazide have additive antihypertensive effects.