The antihypertensive effect of slow-release (SR) nicardipine (40 mg twice a day) and chlorthalidone (25 mg once a day), was evaluated in 36 patients with mild to moderate hypertension by casual and 24-h BP monitoring. After 2-week placebo wash-out, patients were treated for 8 weeks with one of the two drugs, according to a double-blind design. Successively, after other 2 weeks of placebo, they underwent a crossover treatment for other 8 weeks. Both drugs were efficacious in reducing BP. The greater activity of SR nicardipine was revealed by: the effect on casual BP, with the higher number of normalized patients; a greater reduction of 24-h BP; a greater influence on BP variability, assessed by mean standard variation and variation coefficient; the lower levels of linear regression between HR and both systolic and diastolic BP; the reduced per cent incidence of abnormal levels of both systolic and diastolic BP during 24 h. Both drugs were well tolerated, with a low incidence of side effects and absence of alterations of biochemical parameters, a part of 3 cases of ipokalemia induced by chlorthalidone. In conclusion, SR nicardipine is considered to be a safe and active first-choice drug for the treatment of mild to moderate hypertension.