Experience is presented from clinical trials conducted during the development of cilazapril (CLZ) for the treatment of hypertension, in which hydrochlorothiazide (HCTZ) was added to the treatment regimen in patients whose blood pressures did not normalize [sitting diastolic blood pressure (SDBP) ≤ 90 mm Hg] in response to CLZ alone. In 906 mild-to-moderate hypertensives (SDBP = 95-114 mm Hg), adjunct therapy with 12.5-25 mg HCTZ added to 5 mg CLZ provided an additional 3-9 mm Hg reduction in SDBP and increased the normalization rate by 13-27%. Additional efficacy of the combination occurred without any compromise in safety (assessed in 1,189 mild-to-moderate and 99 severe hypertensives and in 9 normal healthy volunteers). Long-term treatment with CLZ and adjunctive HCTZ was well tolerated. The majority of clinical and laboratory adverse events were mild to moderate and not serious; only 5.7% of the mild-to-moderate hypertensives and 3.3% of the severe hypertensives withdrew from the studies due to adverse events and/or intercurrent illness. Therefore, given that the addition of HCTZ to CLZ appears to improve efficacy with no additional safety risk, combining CLZ with HCTZ appears to be a rational clinical choice for patients whose blood pressures do not normalize on CLZ monotherapy.