Background: Leptin modulates ventilation and circulating levels are higher in normal women than men. Objectives: The aim of this study was to compare exercise ventilation and gas exchange in men and women with heart failure (HF) and their relation to circulating leptin concentration. Methods: Consecutive HF patients were studied by cardiopulmonary exercise testing and assay of circulating leptin concentration. Results: Fifty-seven men and 20 women were similar with respect to age, BMI, NYHA class, left ventricular ejection fraction, and peak oxygen consumption (all p > 0.05). Leptin concentration was lower (10.3 +/- 10 vs. 25.3 +/- 16 ng/mL; p < 0.01) and peak exercise ventilatory efficiency (V-E/VCO2) was higher (43 +/- 10 vs. 36 +/- 5; p < 0.01) in men. Leptin concentration was associated with peak exercise V-E/VCO2 (b = -0.35; F = 5.6; p = 0.02). Conclusion: Men have significantly lower circulating leptin concentration and increased ventilatory drive during exercise than women with comparable HF. In men with HF, lower leptin concentration may account for an increased ventilatory drive. (C) 2017 Published by Elsevier Inc.