An open-label study was conducted to evaluate the clinical safety and efficacy of transdermal clonidine as an adjunct to sustained-release (SR) diltiazem (90 mg twice daily) in mild-to-moderate hypertension. Ninety patients with a mean baseline sitting blood pressure of 154/102 mmHg were given 90 mg of diltiazem SR twice daily and transdermal placebo. After four weeks of therapy, 21 patients (23%) had trough sitting diastolic blood pressures (DBP) less than 90 mmHg and were withdrawn. Of the remaining 69 patients (DBP greater than or equal to 90 mmHg), 60 (mean blood pressure 149/98 mmHg) continued to receive 90 mg of diltiazem SR twice daily, to which was added transdermal clonidine, titrated as needed (3.5 cm2, 7.0 cm2, or 10.5 cm2) to achieve blood pressure control. During titration, 58 patients achieved DBP less than 90 mmHg, with a mean blood pressure of 133/84 mmHg. Of these patients, 54 completed an eight-week maintenance period, during which their mean blood pressure was 137/84 mmHg. No significant decrease in pulse or change from baseline in lipid profiles (high-density lipoprotein, low-density lipoprotein, apolipoprotein A-I, apolipoprotein B) was observed with combination therapy. The most frequently reported side effect during maintenance therapy was mild skin irritation at the transdermal application site. One patient was withdrawn because of contact dermatitis. Compliance with the oral twice-daily regimen was variable, with 83% of patients failing to take diltiazem SR at the prescribed dosing intervals 80% to 100% of the time. Transdermal clonidine was worn as directed by 97% of patients. It is concluded that transdermal clonidine in combination with diltiazem SR is safe and effective in the treatment of mild-to-moderate hypertension.