The diuretic and clinical efficacy and safety of piretanide, a new high-ceiling loop diuretic, was determined in patients with mild to moderately severe congestive heart failure. Piretanide (n = 20) administered orally in a daily dosage of up to 24 mg was compared with placebo (n = 18) for 28 days, using a double-blind, randomized, parallel design. Patients were hospitalized during the first 5 days of the study when dosage titration was established and 24-hour fractionated urine collections were obtained. Piretanide caused significant diuresis for 3 hours after ingestion with a natriuretic response noted for up to 6 hours. While occasional kaliuretic response was noted, it did not significantly increase 24-hour urinary potassium excretion. Only one patient treated with the highest allowed dose of piretanide developed mild hypokalemia. An improvement in New York Heart Association functional class status was noted after piretanide therapy. In contrast, patients who received placebo exhibited no significant improvement. BUN increased in nine piretanide-treated patients; two were discontinued from the study because of progressive azotemia. However, there was no significant increase in serum creatinine levels. Other blood, physical, ECG, and audiometric examinations also revealed no significant abnormalities. The study suggests that oral piretanide is a relatively safe and effective diuretic for treating congestive heart failure with a potential advantage of having potassium-sparing properties.