Clearance of bronchial secretions is essential in the management of cystic fibrosis (CF) patients admitted for acute pulmonary exacerbation. Conventional physiotherapy (CPT) is labor-intensive, time-consuming, expensive, and may not be available as frequently as desired during hospitalization. High frequency chest compression (HFCC), which uses an inflatable vest linked to an air-pulse delivery system, may offer an attractive alternative. To study this, we prospectively studied 50 CF patients admitted for acute pulmonary exacerbation who were randomly allocated to receive either HFCC or CPT three times a day. On admission, clinical status and pulmonary function tests (PFT) in the HFCC group were not significantly different from those measured in the CPT group. Significant improvements in clinical status and PFT were observed after 7 and 14 d of treatment, and were similar in the two study groups, leading to patient discharge after similar periods of hospitalization. We conclude that HFCC and CPT are equally safe and effective when used during acute pulmonary exacerbations in CF patients. We speculate that HFCC may provide an adequate alternative in management of CF patients in a hospital setting.