Noninvasive positive pressure ventilation (NIPPV) has been shown to improve exercise tolerance and health-related quality of life in patients with advanced COPD. This study tested the feasibility of nocturnal NIPPV as an additional tool in a hospital-based pulmonary rehabilitation program. This prospective observational trial included forty COPD patients in GOLD stage IV. NIPPV was successfully introduced and accepted during sleep by all patients. All patients received pressure support ventilation for 7.9+/-0.5h per day with an inspiratory support of 17.5+/-4.4 cmH(2)O, and an expiratory pressure of 4.5+/-0.9 cmH(2)O. The outcome of pulmonary rehabilitation in patients receiving nocturnal NIPPV was compared with the results of forty matched control patients who underwent the same program. Rehabilitation with nocturnal NIPPV resulted in the 6-minute walk test and in the longest non-stop walk distance in improvements of 82 and 89 m, respectively, while patients without nocturnal ventilatory support improved by 50 and 51 m (p<0.04 and p<0.03 between groups, respectively). Further significant improvements were found for FEV(1), lung hyperinflation, and blood gases in the NIPPV treated, but not in the control subjects. Health-related quality of life, assessed by the SF-36 questionnaire, improved moderately or largely in patients receiving NIPPV in the categories role-physical, vitality, social function, and mental health. Control subjects improved moderately in vitality only. In conclusion, nocturnal NIPPV is feasible and enhances the effects of pulmonary rehabilitation in advanced stage COPD.