The aim of the present study was to evaluate the acute effects of inspiratory pressure support (IPS) of 5 cmH2O (IPS5) and 10 cmH2O (IPS10) on exercise endurance. Forty-five patients with COPD (mean forced expiratory volume in one second (FEV1)=39±14% pred) performed three constant-load endurance tests on a cycle ergometer at 75% of maximal workload. One test was without IPS, one test with IPS5, and one with IPS10. No statistically significant difference was found in exercise endurance between tests without IPS and IPS5 (4.2±2.6 versus 4.4±2.9 min). In contrast, IPS10 resulted in a statistically significant increase in endurance compared with exercise without IPS (6.32+6.7 versus 4.2±2.6 min), as well as compared with exercise with IPS5 (6.3±6.7 versus 4.4±2.9 min). A wide scatter in individual responses to IPS was found, ranging from a deterioration of 1.6 min (-36%) to an improvement of 16.3 min (+445%). In only 15 patients, the increase in endurance exceeded the upper limit of the 95% confidence interval. Stepwise multiple regression analysis showed that maximal inspiratory pressure was the most important determinant of the increase in exercise endurance due to the application of IPS10. It was concluded that in contrast to inspiratory pressure support of 5 cmH2O, the application of inspiratory pressure support of 10 cmH2O during exercise resulted in a statistically significant improvement in exercise endurance in patients with COPD compared with exercise without inspiratory pressure support. However, on an individual basis, large differences in responses were found. Inspiratory muscle weakness was revealed as a determinant of improvement in exercise endurance due to the application of inspiratory pressure support of 10 cmH2O, explaining only 24% of the variance in outcome.