This multicenter, dose-ranging study evaluated the antihypertensive effectiveness of once-daily administration of fosinopril sodium in 220 patients with supine diastolic blood pressure of 95-115 mm Hg. After a 4-week placebo period, patients were randomly assigned to double-blind therapy with either placebo or 10, 40, or 80 mg fosinopril once daily for 4 weeks. If treatment goals were not met, chlorthalidone 25 mg/day was added for weeks 5 to 8. Thereafter, patients could enter the long-term, open-label phase and receive 10-80 mg/day fosinopril plus chlorthalidone, if needed. After 4 weeks of monotherapy, the average decreases in supine diastolic blood pressure were 9% (10 mg), 11.5% (40 mg), and 12.5% (80 mg) compared with 6% in the placebo group. After 8 weeks, the average decreases, with or without diuretic therapy, were 12.5-18.2%, compared with 10.8% with placebo. Blood pressure continued to be well controlled, and the patients showed no evidence of tachyphylaxis or tolerance through 12-15 months of treatment. Fosinopril was well tolerated. During the short-term phase, no patient withdrew because of adverse events possibly related to fosinopril; during the long-term phase, nine of 148 patients (6.1%) withdrew for that reason. In patients with mild-to-moderate hypertension, once-daily fosinopril (40 and 80 mg) provided significant antihypertensive effects with or without diuretic therapy. The 10 mg dose was effective in some patients and may be considered a starting dose.