Background: Two-legged knee extensor training activates only about half the muscle mass used in traditional cycle ergometer training. With such an exercise model it is possible to achieve a substantial local training effect in spite of a restricted circulatory capacity. The present study sought to investigate the systemic effects of such local training on ventilation and neurohumoral activity in patients with moderate heart failure. Methods and Results: Thirteen male patients with chronic heart failure (age 56 ± 3 years, EF 28 ± 3%) performed two-legged knee extensor exercises (about 4 kg of working muscle) for 15 minutes 3 times a week during 8 weeks at 65–75% of peak VO 2 of a two-legged kick and were compared to a non-training control group (n = 7, age 62 ± 3, EF 27 ± 3%). Before and after the training period VO 2, VCO 2 and the minute ventilation (1/min) were determined at rest and at submaximal and maximal workloads. Also measured before and after training were two-legged knee extensor peak exercise capacity (W), strength (Nm), a 6-minute walking test (m), quadriceps femoris citrate synthase activity, plasma catecholamines, vasoactive amines and blood lactate during submaximal knee extension exercise, and perceived health-related quality of life. After training, VO 2 and VCO 2 were reduced at submaximal exercise by 20–30% ( P < .01) but were unchanged at peak exercise. With training, the two-legged knee extensor peak exercise capacity increased by 38% ( P < .01). The 6-minute walking gait velocity increased by 12% ( P < .01) and skeletal muscle citrate synthase activity by 28% ( P < .01). Training improved the quality of life ( P < .01). After training, VO 2 ( P < .001), VCO 2 ( P < .001) and minute ventilation ( P < .001) were reduced at the workload corresponding to the maximal workload before training. The ratio minute ventilation/VO 2 was reduced ( P < .05) after training at the before-training maximal workload. No change was observed in the control group with regard to two-legged peak exercise capacity or peak VO 2. Plasma NPY was reduced both at rest and at submaximal exercise by 35% ( P < .01), whereas noradrenaline was reduced only during exercise ( P < .05). Conclusions: Local muscle training is effective in stable chronic heart failure and can improve, in addition to exercise capacity and quality of life, the ventilatory response, and decrease the sympathetic stress.