Objectives: The authors hypothesized that the women enrolled in the HF-ACTION (Heart Failure-A Controlled Trial Investigating Outcomes of Exercise TraiNing) trial and randomly assigned to exercise training (ET) would improve functional capacity as measured by peak oxygen uptake (VO2) compared with those in the usual care group. Furthermore, they hypothesized that the improvement in peak VO2 would correlate with prognosis. They explored whether exercise had a differential effect on outcomes in women versus men. Background: There is less evidence for the benefit of ET in women with heart failure (HF) compared with men because of the small numbers of women studied. Methods: HF-ACTION was a randomized trial of ET versus usual care in 2,331 patients with class II-IV HF and a left ventricular ejection fraction of≤35%. Sex differences in the effects of randomized treatment on clinical outcomes were assessed through the use of a series of Cox proportional hazards models, controlling for covariates known to affect prognosis in HF-ACTION. Results: Women had lower baseline peak VO2 and 6-min walk distance than did men (median, 13.4 vs. 14.9 ml/min/kg and 353 vs. 378 m, respectively). An increase in peak VO2 at 3 months was present in women and men in the ET group (mean ± SD; median, 0.88 ± 2.2, 0.80 and 0.77 ± 2.7, 0.60, respectively, women vs. men; p= 0.42). Women randomly assigned to ET had a significant reduction in the primary endpoint, (hazard ratio: 0.74) compared with men (hazard ratio: 0.99) randomly assigned to ET, with a significant treatment-by-sex interaction (p= 0.027). Conclusions: Although there is no significant difference between men and women in the effect of ET on peak VO2 change at 3months, ET in women with HF is associated with a larger reduction in rate of the combined endpoint of all-cause mortality and hospital stay than in men. © 2014 American College of Cardiology Foundation.