We evaluated a new slow-channel calcium-blocking agent, diltiazem hydrochloride, in 10 patients with documented fixed coronary artery disease who had reproducible angina and greater than or equal to 0.1 mV ST segment depression on ECG treadmill exercise testing after 1 week of single-blind placebo administration. Subsequently, over the next 6 weeks, either diltiazem (30 mg/tablet) or placebo were administered for 1 week each in a randomized double-blind triple crossover design, as one tablet four times a day, two tablets three times a day or two tablets four times a day, for a total diltiazem dose of 120, 180 and 240 mg/day, respectively. Treadmill (electrocardiogram) exercise testing was performed at the end of each week. Only diltiazem at 240 mg/day increased significantly the time to angina pectoris (P less than 0.05), time to ST segment depression (P = 0.01), time to maximal exercise (P less than 0.02), and heart rate at maximal exercise (P less than 0.05) without effecting significantly the maximal rate-pressure product compared to the corresponding placebo values. In addition, using only the diltiazem data, a significant high dose response was observed for time to angina (P less than 0.05), ST segment depression (P less than 0.005), and maximal exercise (P less than 0.025). No adverse reactions were reported during the study. Therefore, we conclude that 240 mg/day of diltiazem improves significantly exercise performance in patients with angina pectoris due to fixed coronary artery disease and adverse effects, rarely, if ever, occur at this dosage.