The efficacy and tolerability of amlodipine (5 mg, once daily), nifedipine retard (20 mg, twice daily), and placebo were compared in a multicenter, three-way, crossover study involving 97 patients with mild-to-moderate hypertension. Each patient underwent three, 2-week treatment periods separated by 2-week washout periods without therapy. Comparable and significant (p < 0.05) blood pressure reductions were observed after amlodipine and nifedipine retard when compared with placebo, except in the case of supine systolic blood pressure with nifedipine retard. A significantly greater incidence of treatment-related side effects was observed with nifedipine retard (41%) compared with amlodipine (27%, p < 0.05) or placebo (16%, p < 0.01). Amlodipine treatment was associated with significantly fewer reports of headache and flushing than nifedipine retard (p < 0.05). The lower incidence and reduced severity of vasodilator side effects associated with amlodipine resulted in fewer withdrawals and a better overall tolerability profile.