Objectives. The purpose of this study was to determine the effectiveness and safety of diltiazem or lisinopril for treatment of hypertension after heart transplantation. Background. Systemic hypertension is common after heart transplantation, and to date there are no randomized, prospective multicenter treatment trials. Methods. Members of the Cardiac Transplant Research Database Group developed and implemented a prospective, randomized multicenter trial of the effectiveness and safety of diltiazem or lisinopril in the treatment of hypertension in cyclosporine-treated patients after heart transplantation. Results. One hundred sixteen patients with hypertension (blood pressure ≥140/90 mm Hg) after heart transplantation were randomized for ≥3 months of treatment. Of 55 diltiazem-treated patients, 21 (38%) were responders (diastolic blood pressure <90 mm Hg), 23 (42%) were nonresponders (diastolic blood pressure ≥90 mm Hg), and 11 (20%) were withdrawn from the study. Of 61 lisinopril-treated patients, 28 (46%) were responders, 22 (36%) were nonresponders, and 11 (18%) were withdrawn. There was no difference in baseline characteristics or percent responders between the two groups. Systolic pressure decreased from 157 ± 2.3 to 130 ± 2.0 mm Hg (mean ± 1 SEM) in the diltiazem-treated responders and from 153 ± 2.1 to 127 ± 2.7 mm Hg in the lisinopril-treated responders (p < 0.0001). Diastolic pressure decreased from 100 ± 0.9 to 85 ± 1.6 mm Hg in the diltiazem-treated responders and from 100 ± 1.0 to 84 ± 2.0 mm Hg in the lisinopril-treated responders (p < 0.0001). There were a total of 35 reported adverse events, 22 of which led to withdrawal of the patient from the study. All drug-related side effects were considered minor and resolved with discontinuation of the drug. Conclusions. These results indicate that both diltiazem and lisinopril are safe for treatment of hypertension after heart transplantation, although titrated monotherapy with either drug controlled the condition in <50% of patients.