We compared the efficacy of manual and mechanical chest percussion during hospitalization for acute exacerbations of cystic fibrosis by evaluating changes in spirometry values. Fifty-one participants were randomly assigned to receive manual or mechanical chest percussion three times a day. Twenty-two participated during one subsequent admission and were assigned to the opposite form of chest percussion. The two groups were equal in severity of illness (mean National Institutes of Health score (+/- SEM): manual = 66.7 +/- 2.2; mechanical = 35.8 +/- 2.2; p = not significant). Mean improvement in forced expiratory volume at 1 second, forced vital capacity, and forced expiratory flow between 25% and 75% of forced vital capacity (+/- SEM) for manual percussion was 32.6% +/- 7%, 27.2% +/- 5%, and 38.1% +/- 10%, and for mechanical percussion was 28.5% +/- 4%, 28.7% +/- 4%, and 25.1% +/- 8%, respectively; p = not significant. Our participants did not prefer mechanical chest percussion. Although equal efficacy of outpatient therapy remains to be proved, this study suggests that patients can be encouraged to use the form of chest percussion that they prefer.