A double-blind, crossover study was carried out to compare the antihypertensive efficacy of the long-acting ACE inhibitor trandolapril 1 mg administered once daily and 0.5 mg twice daily in 31 patients with mild to moderate essential hypertension. After randomization, patients entered a single-blind placebo period of 4 weeks. After a double-blind treatment of 4 weeks with either of the dosage regimens, patients were then crossed over to the alternate regimen for the last 4 weeks of the study. Conventional BP and heart rate were measured on each visit and ambulatory BP monitoring was done at baseline and at the end of each treatment phase. Conventional as well as 24-hour and awake ambulatory systolic and diastolic BPs were significantly (P < 0.001) and almost identically decreased by both once- and twice-daily formulations. Moreover, the clinical response rates (reduction in seated diastolic BP > or = 10% or diastolic BP < or = 90 mm Hg) were similar with both treatment regimens (42% vs. 45% with the once- and twice-daily formulations, respectively). However, trandolapril twice daily exerted a significantly (P = 0.03) greater antihypertensive effect on systolic BP during sleep as compared with the once-daily formulation. Due to the fact that the minimal effective dose was used in this trial, further studies with higher doses should demonstrate effective 24-hour control of BP as described with other long-acting ACE inhibitors. In addition, our results suggest that ambulatory BP measurements should be done in dose-response studies.