The cardiovascular effects of bupropion hydrochloride and nortriptyline were compared in a double-blind, randomized, 6-week trial in adult outpatients with major depression. After a 1-week placebo phase, 58 patients were randomized to treatment with bupropion (225-450 mg/day) and 57 to nortriptyline (75-150 mg/day). Nortriptyline-treated patients had statistically significant heart rate increases at each assessment as determined by RR intervals on electrocardiogram (14.5-18 bpm). Bupropion-treated patients had small but statistically significant increases in supine diastolic blood pressure of 5.6 mm Hg on day 7 and 7.5 mm Hg on day 28. A few patients in each treatment group had orthostatic changes, but only nortriptyline-treated patients had symptomatic orthostatic hypotension. A slowing of cardiac conduction and possibly of rate-corrected repolarization occurred in patients treated with nortriptyline that did not occur in patients treated with bupropion. Compared to nortriptyline, bupropion appears to have a wider safety margin with regard to cardiovascular effects. This may be particularly true in the elderly, in patients with preexisting cardiovascular disease, or in overdose.