Acute administration of nifedipine (NIF), a calcium entry blocker (CEB), in animals reduces the hypotensive effect of clonidine (CLN), an alpha-adrenergic agonist. In order to evaluate possible negative interactions between NIF and CLN in man during chronic treatment with these drugs, 12 patients with mild to moderate uncomplicated essential hypertension received either NIF (20 mg twice daily), CLN (0.25 mg once daily), the two drugs together at the same doses, or their matched placebos for a 2-week period each. NIF (-13.5% versus placebo) and CLN (-10.2% versus placebo) decreased blood pressure significantly and when combined, blood pressure was further decreased (-17.1% versus placebo). Heart rate was increased by NIF and NIF + CLN but unchanged by CLN alone. Plasma renin activity (PRA) tended to increase with NIF, decreased with CLN (P < 0.05) and was unchanged with NIF + CLN. Plasma aldosterone did not vary during any of the phases of the trial. These results indicate that NIF and CLN do not interact negatively on blood pressure control in essential hypertensive subjects.