BACKGROUND: Positive expiratory pressure is used for airway clearance in cystic fibrosis (CF) patients. Hypertonic saline (HTS) aerosol increases sputum expectoration volume and may improve respiratory secretions properties. Continuous positive airway pressure (CPAP) may also be used to maintain airway patency and mobilize secretions. To evaluate if CPAP would increase the beneficial clearance effect of HTS in subjects with CF, we investigated the effects of CPAP alone and CPAP followed by HTS on sputum physical properties and expectoration volume in CF subjects. METHODS: In this cross-over study, fifteen CF subjects (18 ± 7 years) were randomized to interventions, 48-hrs apart: directed coughs (Control), CPAP at 10 cmH₂O, HTS 7%, and both CPAP and HTS (CPAP+HTS). Sputum collection was performed at baseline and after interventions. Expectorated volume was determined and in vitro sputum properties were analyzed for contact angle and cough clearability. RESULTS: There were no significant differences between any treatment in arterial blood pressure, heart rate, or pulse oximetry, either between the two time points. HTS and CPAP+HTS improved cough clearability by 50% (P = .001) and expectorated volume secretion by 530% (P = .001). However, there were no differences between control and CPAP on sputum contact angle, cough clearability or volume of expectorated secretion. CONCLUSION: CPAP alone had no effect on mucus clearance, sputum properties or expectorated volume, and did not potentiate the effect of HTS alone in CF subjects.