Two multicenter, double-blind, randomized studies were performed to determine the antihypertensive efficacy and effects on laboratory values of a new, shorter-acting formulation of metolazone in patients with mild to moderate hypertension. After baseline placebo-control periods, 105 patients were randomly assigned to receive single daily doses of either placebo or 0.5, 1.0, or 2.0 mg of the new formulation of metolazone for six weeks in one study, and 164 patients were randomized to receive 0.5, 1.0, or 2.0 mg of the new formulation of metolazone or 2.5 mg of the older, long-acting metolazone in the other. Mean blood pressure reductions in all three metolazone groups were statistically and clinically significant. Blood pressures of 51% to 58% of patients in the 0.5-mg metolazone group were controlled (diastolic blood pressure less than 90 or a fall of greater than or equal to 10 mmHg from baseline). Reductions in mean serum potassium levels were dose-related. We conclude that 0.5 mg of metolazone is safe and effective therapy for hypertension; it will significantly reduce systolic and diastolic blood pressure and minimizes changes in laboratory test values.