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Summary Background Non-invasive ventilation and exercise training might prove beneficial in the management of COPD patients. Objetive to compare the combined use of exercise training and non-invasive ventilation with the two interventions separately in chronic respiratory failure due to chronic obstructive pulmonary disease. As primary objective exercise capacity and secondary objectives gas exchange, peripheral muscle strength, BODE index, quality of life and systemic inflammatory response. Methods Forty-five patients with severe chronic obstructive pulmonary disease were randomized into three groups for an intervention of 12 weeks: exercise training alone, ventilation alone and combined treatment. We assessed exercise capacity, pulmonary function, BODE index, perception of dyspnoea, quality of life and several biomarkers. Results All exercise capacity parameters improved after training and the combined treatment. In addition, peripheral muscle strength and six-minute walk distance increased after ventilation. We found differences between the combined group and the ventilation group in submaximal effort and in oxygen consumption. Changes in respiratory function were observed in blood gases that improved after ventilation and the combined treatment, with differences between these groups. BODE index, perception of dyspnoea and quality of life improved in all three groups without differences between groups. Levels of interleukin 8 and tumour necrosis factor α decreased after ventilation, and interleukin 8, C-reactive protein and surfactant protein D decreased after training, while all four of these markers fell after the combined treatment. No differences between groups were found. Conclusions The combination of ventilation and exercise training had greater benefits than the separate treatments: improvements were observed in both blood gases and the levels of more biomarkers decreased. In addition, submaximal exercise capacity increased in all groups. The improvements seen in BODE index, perception of dyspnoea and quality of life were similar in all groups.