Background. We aimed to determine the role of skeletal muscle mitochondrial ATP production rate (MAPR) in relation to exercise tolerance following resistance training in CHF. Methods and Results. Thirteen CHF patients (NYHA functional class 2.3 ± 0.5; LVEF 26 ± 8%; age 70 ± 8 years) underwent testing for VO2peak, and resting vastus lateralis muscle biopsy. Patients were then randomly allocated to 11 weeks of RT, (n = 7) or continuance of usual care (C, n = 6) following which testing was repeated. Muscle samples were analysed for MAPR, metabolic enzyme activity and capillary density. VO2peak and MAPR in the presence of the pyruvate and malate (P+M) substrate combination, representing carbohydrate metabolism, increased in RT (p<0.05) and decreased in C (p<0.05) with a significant difference between groups (VO2peak p = 0.005; MAPR p = 0.03). There was a strong correlation between the change in MAPR and the change in VO2peak over the study (r = 0.875; p < 0.0001), the change in MAPR accounting for 70% of the change in VO2peak. Conclusions. These findings suggest that mitochondrial ATP production is a major determinant of aerobic capacity in CHF patients and can be favourably altered by muscle trengthening exercise.