INTRODUCTION Exercise training is recommended for comprehensive management of patients with heart failure and reduced ejection fraction (HFrEF). However, limited exercise capacity prevents many patients from gaining optimal training benefit. Given eccentric cycling is well tolerated in HFrEF, and enables greater power output, we hypothesized that eccentric cycling training would result in superior functional outcomes than concentric cycling training when the interventions were matched for heart rate (HR). METHODS Forty-five participants (9♀, 57±13 y; BMI 27±5 kg/m2) with HFrEF (ejection fraction 33±10%, New York Heart Association class II) were randomized in a 1:1 superiority clinical trial to either eccentric cycling training (ET, n = 25) or concentric cycling training (CT, n = 20). Each intervention involved 2-weeks of familiarization and 12-weeks of training at matched relative intensity (40-80% of HR reserve), twice weekly. Primary outcome was peak oxygen consumption (V̇O2peak), secondary outcomes included 6-minute walk, functional lower extremity strength and health-related quality of life (Minnesota Living with Heart Failure, MLHF). RESULTS Repeated measures ANOVA revealed significant interaction effects for 6-min walk (ET 476±77 to 547±80 m vs CT 485±106 to 516±113 m, P=0.015), 30s sit-to-stand (ET 12±3 to 16±3 repetitions vs CT 13±4 to 14±3 repetitions, P=0.002), and timed up-and-go (ET 7.2±1.2 to 6.2±1.1 s vs CT 7.6±1.5 to 7.3±1.9 s, P=0.019). There were significant time effects for V̇O2peak (ET: 17.7±4.8 to 19.1±5.2 ml/kg/min and CT 17.4±6.0 to 19.8±6.0 ml/kg/min, P<0.001), and MLWHF (ET 31±24 to 23±16 and CT 32±19 to 27±16, P=0.003). CONCLUSION When matched for heart rate to control cardiovascular burden, ET demonstrated superior effect in functional capacity, and similar benefits in aerobic capacity (V̇O2peak) and health-related quality of life, when compared to CT. ET is a novel and efficacious approach for clinical benefit in highly compromised HFrEF patients, who represent a challenge in terms of exercise prescription.