We investigated whether ranolazine therapy improves exercise-induced angina pectoris and myocardial ischemia compared with placebo or with standard doses of atenolol in patients who had chronic angina and evaluated the effects on hemodynamics at rest and during exercise. In this trial, 158 patients who had symptom-limited exercise discontinued beta-blocker therapy and were randomized into a double-blind, 3-period, crossover study of 400 mg of immediate-release ranolazine 3 times daily, 100 mg/day of atenolol, or placebo, each administered for 1 week. Exercise tests were administered at the end of each treatment period. Therapy with ranolazine or atenolol produced statistically significant improvement in all 3 exercise end points compared with placebo. Compared with atenolol therapy, ranolazine therapy resulted in significantly longer total exercise duration and was statistically indistinguishable from atenolol for time to onset of angina and ST-segment depression. Except for a modest increase in systolic blood pressure at peak exercise during ranolazine therapy, hemodynamic measurements did not differ significantly during ranolazine and placebo therapies. In contrast, atenolol significantly decreased blood pressure, heart rate, and rate-pressure product at rest and during exercise compared with placebo or ranolazine. In conclusion, ranolazine therapy prolonged exercise duration and decreased exercise-induced ischemia and angina with quantitative effects equal to or greater than those with atenolol. Unlike atenolol, the anti-ischemic and antianginal effects of ranolazine occurred without decreases in blood pressure, heart rate, or rate-pressure product.