The effect of sotalol on exercise tolerance and incidence of arrhythmias was studied in 30 patients with hypertrophic cardiomyopathy (HCM). In this short-term, double-blind, crossover study, exercise time on sotalol (320 mg/day) was significantly longer than on placebo (10.6 ± 4.0 vs. 9.4 ± 3.6 min; p < 0.01). Sotalol eliminated supraventricular arrhythmias in 6 of 7 patients (p < 0.03) and suppressed ventricular arrhythmias in 7 of 13 patients in whom they were present on placebo (p < 0.05). Ventricular tachycardia was abolished in 4 of 8 patients, but appeared during sotalol treatment in 1 patient who was free of repetitive arrhythmias on placebo. Twenty-five patients who had better exercise tolerance on sotalol than on placebo and did not experience aggravation of arrhythmia entered a 6-month prospective, open-label treatment with sotalol (160-480 mg/day, mean ± SD377 ± 94). One patient was withdrawn after 1 month because of bronchospasm. Mean exercise time improved from 9.8 ± 3.6 min on placebo to 12.7 ± 3.2 min (p < 0.01) after 6 months of treatment with sotalol. During the prospective follow-up, sotalol abolished ventricular tachycardia in all 6 patients after 1 month (p = 0.022), and in 4 of 6 patients (p > 0.2) after 6 months of treatment. It is concluded that sotalol significantly improves exercise tolerance and is effective in suppressing both supraventricular and ventricular arrhythmias in patients with HCM.