Poor compliance is a principal cause of treatment failure in hypertensive patients. Once-daily dosing improves compliance, but 24-h antihypertensive activity should be provided. The compliance, efficacy, and safety of amlodipine and nifedipine slow-release (SR) were compared in patients with mild-to-moderate essential hypertension recruited among 24 centers in France. After a 2-week washout period, 103 patients were randomized to 12 weeks of 5 to 10 amlodipine mg once daily (n = 55) or 20 mg nifedipine SR twice daily (n = 48). Compliance was calculated by electronic drug monitoring. Efficacy was measured by ambulatory and casual BP recordings. Patients receiving amlodipine demonstrated better compliance than patients receiving nifedipine SR with respect to compliance index (the total number of doses taken divided by the total number of doses prescribed, expressed as a percentage; 98.3% v 87%; P < .0001), days on which the correct number of doses were taken (92.5% v 74.8%; P < .0001), and prescribed doses taken on schedule (88.7% v 71.6%; P < .0001). Absolute and relative therapeutic coverage were higher in patients receiving amlodipine than nifedipine SR (P < .0001). Mean SBP and DBP decreased equally in both groups, although amlodipine offered better BP control compared with nifedipine SR at specific times of day. Fewer patients had high nocturnal SBP with amlodipine (39.3%) than nifedipine SR (71.4%; P = .042). Adverse events and treatment withdrawals occurred less frequently in amlodipine-treated patients than in nifedipine SR-treated patients. Amlodipine (5 to 10 mg) once daily provides improved compliance, better 24-h BP control, and fewer adverse events than 20 mg nifedipine SR twice daily in patients with mild-to-moderate hypertension.