Objective: To examine the efficacy and tolerability of the neutral endopeptidase inhibitor, candoxatril (UK 79,300) as monotherapy in essential hypertension. Design: Double-blind, placebo-controlled, parallel-group study of 28 days' duration. Setting: Three hospital outpatient departments participating in the Glasgow Blood Pressure Clinic (Glasgow, UK). Patients: Forty patients with essential hypertension with diastolic blood pressure 95–114 mmHg after a 2–4 week placebo run-in period. Interventions: Twenty-eight days' treatment with candoxatril 200 mg twice daily or matching placebo capsules. Main outcome measures: Changes in supine and erect blood pressure, and volunteered side effects during double-blind treatment. Results: When measured at the end of the dose interval, the fall in supine blood pressure following candoxatril was not significantly greater than that after placebo. Compared with placebo, a significant effect for candoxatril was seen only for systolic blood pressure in the erect posture; the fall in erect diastolic blood pressure attributable to candoxatril was insignificant. Median plasma atrial natriuretic peptide concentration increased in candoxatril-treated patients and decreased in the placebo group. No stimulation of the renin—aldosterone axis was seen. There was a non-significant trend towards greater urinary excretion of cyclic guanosine monophosphate after candoxatril. Mean plasma concentrations of candoxatrilat (UK 73,967 — the active metabolite of candoxatril) reached a peak of 1010±437 ng/ml after acute dosing, and 1328±405 ng/ml after chronic dosing; time to maximum concentration was 2 h in each case. Candoxatril was well-tolerated; numbers of adverse events did not differ between active treatment and placebo. Conclusions: Although atrial natriuretic peptide levels were significantly increased, candoxatril 200 mg twice daily for 28 days did not produce a clinically relevant fall in blood pressure. Our results cast some doubt upon the role of neutral endopeptidase inhibition in the treatment of unselected hypertensive patients.