Background Skeletal muscle wasting is associated with altered catabolic/anabolic balance and poor prognosis in patients with chronic heart failure (CHF). This study evaluated catabolic and anabolic abnormalities in relation to disease severity in CHF patients. Methods Forty-two stable CHF patients (34 men; aged 56±12 years, body mass index, 27±5 kg/m2) receiving optimal medical treatment underwent incremental symptom-limited cardiopulmonary exercise testing on a cycle ergometer. Blood samples were drawn within 10 days to determine serum cortisol, plasma adrenocorticotropin (ACTH), and serum dehydroepiandrosterone sulfate, insulin-like growth factor 1, growth hormone, and total testosterone in men. Results Patients with higher cortisol levels presented with impaired peak oxygen uptake (Vo2 peak: 18.3±3.9 vs 14.2±3.7 ml/kg/min, p<0.01), ventilatory (Ve) response to exercise (Ve/carbon dioxide output [Vco2] slope: 36±6 vs 30±5, p<0.01), and chronotropic reserve ([peak heart rate [HR] – resting HR/220 – age – resting HR]×100%: 40±19 vs 58±18, p=0.01) compared with those with lower serum cortisol. Cortisol was inversely correlated with Vo2 peak, (r = −0.57; p<0.01) and was correlated with Ve/Vco2 slope (r = 0.47; p<0.01) and chronotropic reserve (r = 0.44; p = 0.017). In multivariate regression analysis, cortisol was an independent predictor of Vo2peak (R2 = 0.365, F = 12.5, SE = 3.4; p≤0.001) and Ve/Vco2 slope (R2 = 0.154; F = 8.5; SE = 5.96; p = 0.006), after accounting for age, body mass index, sex, CHF etiology, creatinine, left ventricular ejection fraction, and ACTH in all patients. In men, cortisol and dehydroepiandrosterone levels were both independent predictors of Vo2peak (R2 = 0.595, F = 24.53, SE = 2.76; p<0.001) after accounting also for all measured hormones, whereas cortisol remained the only independent predictor of Ve/Vco2 slope (R2 = 0.133; F = 6.1; SE = 6.2; p = 0.02). Conclusions Enhanced catabolic status is significantly associated with exercise intolerance, ventilatory inefficiency, and chronotropic incompetence in CHF patients, suggesting a significant contributing mechanism to their limited functional status.