In this multicenter, placebo-controlled, double-blind, 4 × 3 factorial design study, 1,162 patients randomized into 12 parallel groups received either placebo (n = 97), cilazapril (CLZ 0.5, 5, or 10 mg; n = 288 total), hydrochlorothiazide (HCTZ 12.5 or 25 mg; n = 198 total), or one of the six possible combinations of the two drugs (n = 579 total) given orally once daily for 4 weeks. The mean decrease from baseline in predose (i.e., 24 h postdose) sitting diastolic blood pressure (SDBP) was statistically significantly (p < 0.01) greater for all combinations studied compared to placebo, as well as to their respective monotherapy components. Synergistic antihypertensive effects were noted for the 5/12.5 mg CLZ/HCTZ combination therapy. The normalization (SDBP ≤ 90 mm Hg) rate of the 5/12.5 mg CLZ/HCTZ combination was essentially additive with respect to the component monotherapies. The tolerability profile of the CLZ/HCTZ combination was similar to its respective components and comparable to placebo. The CLZ/ HCTZ group reported low serum potassium (K<sup>+</sup>) and high serum uric acid less frequently than the HCTZ group. Therefore, the CLZ/HCTZ combination (5 mg/l2.5 mg) is an option for hypertensive patients not responding to single drug CLZ therapy.