We performed a double-blind controlled crossover trial of perhexiline maleate versus identical placebo in daily doses of 100-400 mg in 20 male patients who were severely limited with angina pectoris despite therapy with beta-adrenoreceptor blockers. All patients had documented coronary artery disease and were awaiting coronary artery bypass grafting. Beta-blocker therapy was continued unchanged. A significant response compared to placebo was evident after 100 mg of perhexiline, and incremental therapeutic effects were evident up to 400 mg. The mean weekly angina rate fell from 18.2 +/- 2.8 basal to 6.2 +/- 1.5 on 200 mg (P less than 0.05) to 2.8 +/- 0.9 on 400 mg perhexiline (P less than 0.05). Nitroglycerin consumption fell in parallel. The mean exercise duration increased from 261 +/- 57 sec to 384 +/- 75 sec (P less than 0.05). Five patients became asymptomatic on perhexiline, and the number of pain-free days increased 100% (P less than 0.01) compared to placebo. No patient experienced hypotension or heart failure. This study shows that the addition of perhexiline to beta-adrenoreceptor antagonists in patients with severe angina pectoris is effective and represents an alternative therapy.