Lisinopril is a long-acting converting-enzyme inhibitor. A 52-week study was undertaken to compare the antihypertensive efficacy and safety of lisinopril, hydrochlorothiazide (HCTZ), and a combination of the two drugs in 24 patients with a sitting diastolic blood pressure (DBP) of 90 to 120 mm Hg. After a four-week single-blind placebo-washout phase, ten patients received lisinopril, ten received HCTZ, and four received the combination in increasing doses in a double-blind fashion for the next 12 weeks. The target blood pressure was less than 90 mm Hg DBP and a decrease of at least 10 mm Hg. For the next 12 weeks, the responders continued to receive the same medications; however, the nonresponders from the two groups received the combination, increasing the number of patients receiving both to 13. The DBP was controlled in eight of the ten patients with lisinopril, three of the ten patients with HCTZ, and 11 of 13 (four original and nine nonresponders) with the combination. For the next 28 weeks, 17 patients agreed to continue into a single-blind phase, during which blood pressure was controlled in six of the seven patients who were treated with lisinopril alone and nine of ten who received the combination. The heart rate rose significantly in the HCTZ-treated patients during the short-term treatment and decreased significantly in those treated with lisinopril during the long-term phase. Side effects were more frequent in patients receiving the combination but were always mild and subsided spontaneously. Lisinopril appeared to be more effective than HCTZ as a step-1 drug, and the combination was superior to either agent alone.