This study describes sustained efficacy and safety of lofexidine in hypertensive patients. Twenty-one male patients (mean age 55 +/- 9 yr) who had previously completed a short-term trial of lofexidine entered this open-label trial. The daily dose of lofexidine was titrated over three months to a maximum of 1.6 mg or an erect diastolic blood pressure less than 90 mm Hg. Hydrochlorothiazide was added when necessary. Thereafter, each patient was evaluated for blood pressure (BP) response, compliance, side effects, hepatic, renal, or hematological abnormalities every three months for two years. Sustained BP reduction with lofexidine was achieved but not without concomitant diuretic therapy. There were no clinically important changes in heart rate or hepatic, renal, or hematological profiles. Side effects were frequent but severe enough to warrant discontinuation in only four patients. The side-effect profile was similar to that of clonidine. We recommend concurrent diuretic use to maximize effectiveness of lofexidine.