Heart failure (HF) is characterized by decreased exercise capacity, attributable to neurocirculatory and skeletal muscle factors. Cardiac resynchronization therapy (CRT) and exercise training have each been shown to decrease muscle sympathetic nerve activity (MSNA) and increase exercise capacity in patients with HF. We hypothesized that exercise training in the setting of CRT would further reduce MSNA and vasoconstriction and would increase Ca²⁺-handling gene expression in skeletal muscle in patients with chronic systolic HF. Thirty patients with HF, ejection fraction <35% and CRT for 1 mo, were randomized into two groups: exercise-trained (ET, n = 14) and untrained (NoET, n = 16) groups. The following parameters were compared at baseline and after 4 mo in each group: V̇o_{2 peak}, MSNA (microneurography), forearm blood flow, and Ca²⁺-handling gene expression in vastus lateralis muscle. After 4 mo, exercise duration and V̇o_{2 peak} were significantly increased in the ET group ( P = 0.04 and P = 0.01, respectively), but not in the NoET group. MSNA was significantly reduced in the ET ( P = 0.001), but not in NoET, group. Similarly, forearm vascular conductance significantly increased in the ET ( P = 0.0004), but not in the NoET, group. The expression of the Na⁺/Ca²⁺ exchanger ( P = 0.01) was increased, and ryanodine receptor expression was preserved in ET compared with NoET. In conclusion, the exercise training in the setting of CRT improves exercise tolerance and neurovascular control and alters Ca²⁺-handling gene expression in the skeletal muscle of patients with systolic HF. These findings highlight the importance of including exercise training in the treatment of patients with HF even following CRT.