To test the dose responses of piretanide, ramipril, and their combination in patients with essential hypertension, a prospective, randomized, double-blind, placebo-controlled trial was conducted in 480 patients. Twelve separate groups were studied: placebo, piretanide 3 mg, piretanide 6 mg, ramipril 2.5 mg, ramipril 5 mg, ramipril 10 mg, and their combinations, as single daily morning doses. Patients were randomized after a 2-week run-in period without drugs; treatment was given for 6 weeks. A dose response compared with placebo was found for both drugs; the combination was more effective than either drug alone. Piretanide 6 mg, combined with ramipril 5 mg, provided optimal blood pressure reduction. Self-reported adverse effects of both drugs and their combinations did not exceed those reported for placebo. A surface analysis suggested that piretanide primarily reduced systolic blood pressure, whereas ramipril was more effective in reducing diastolic blood pressure. The data attest to a combined efficacy of piretanide and ramipril in decreasing arterial blood pressure.