Ranolazine reduces angina frequency and increases exercise capacity. We hypothesized that exercise training with ranolazine would allow subjects to train at greater intensities, resulting in greater improvements in exercise capacity, physical activity, and health-related quality of life (HRQOL). In a pilot study, subjects with chronic stable angina pectoris were randomized to ranolazine (n = 13) or placebo (n = 16). After a 2-week drug titration period, subjects participated in a 12-week exercise program. Peak VO2, physical activity (via accelerometer), and HRQOL were assessed before and after training. After exercise training, peak VO2increased twice as much with ranolazine (2.1 ± 3.4 ml/kg/min) as with placebo (0.9 ± 1.5) (both p <0.05). After exercise training, both groups significantly improved HRQOL score (p <0.05); however, the improvement with ranolazine (19 ± 21) was almost 50% greater than with placebo (13 ± 18). There was a significant decrease in maximal heart rate after training with ranolazine but not with placebo (group difference, p = 0.04). Oxygen pulse (peak VO2/peak HR) increased in both groups after training; but, the increase was 4 times greater with ranolazine - resulting in a significant difference between groups (p = 0.044). In conclusion, patients with angina, the addition of ranolazine to an exercise program may improve aerobic fitness, physical activity, and HRQOL beyond the results of an exercise training program alone. Exercise training with ranolazine led to significantly greater increases in oxygen pulse, which is significantly correlated with stroke volume and is an independent predictor of mortality.