The aim of this study was to determine the benefits of CPAP applied during exercise in patients with cystic fibrosis (CF). A total of 33 CF patients with a wide range of lung function were studied. Pulmonary function tests were measured at rest. Endurance tests (80% of previously determined Wpeak) were performed on a bicycle ergometer with and without CPAP (5 cm H2O). Oxygen saturation (SaO2) was monitored by oximetry. Transdiaphragmatic pressure (Pdi) was measured in 7 patients. We found significant correlations between indices of disease severity (NIH score, FEV1, % of predicted, and RV/TLC) and the effects of CPAP on VO2, Pdi, and dyspnea score. CPAP reduced isotime (defined as the last common minute of exercise) VO2 and dyspnea in those patients with more severe lung disease, but these values tended to increase slightly in the patients with only mild lung disease. The change in dyspnea score related to changes in endurance time and VO2. In many patients isotime SaO2 was improved with CPAP, with the largest changes observed in those patients with severe disease. The decreases in VO2, Pdi, and dyspnea score with CPAP in patients with severe lung disease suggest that CPAP can reduce the work of breathing and increase exercise tolerance in patients with CF. These beneficial effects of CPAP during exercise in CF patients are related to disease severity.