OBJECTIVES: To investigate the impact of pulmonary exacerbations on the health-related quality of life (HRQOL) of patients with cystic fibrosis (CF) and to elucidate factors that are associated with changes in HRQOL post-exacerbation. STUDY DESIGN: Participants completed questionnaires at a pre-exacerbation visit, at the beginning of the exacerbation, and at the post-exacerbation visit. To measure HRQOL, we used the Child Health Questionnaire-Parent Form (PF-50) and the Medical Outcomes Study Short Form-36 (SF-36). We examined demographic, clinical, and treatment-related predictor variables for association with change in Physical Summary (PhS) and Psychosocial Summary (PsS) HRQOL scores after an exacerbation. RESULTS: We collected data from 48 subjects. Patients experiencing exacerbations who were treated as outpatients had a mean (SD) age of 19.5 (12.7) years and a mean pre-exacerbation forced expiratory volume in 1 second (FEV(1)) of 70% (36%) of predicted; 53% were female. Patients treated as inpatients had a mean age of 14.6 (5.5) years and a mean FEV(1) of 56% (24%); 56% were female. In univariate analyses, exacerbations were associated with a statistically significant decrease in FEV(1) (-10.0%) and PhS scores (-4.5 points). PsS scores did not significantly change with exacerbations (-0.7 points). In multivariable analyses examining change between pre-exacerbation and post-exacerbation visits, no variables were significantly associated with change in PhS scores. However, not being hospitalized for the exacerbation was associated with deterioration in PsS scores, and being hospitalized was associated with improvement in PsS scores (beta coefficient: 9.4; P <.01) by the post-exacerbation visit. Results were similar from the exacerbation to the post-exacerbation visit. CONCLUSION: In patients with CF, on average, pulmonary exacerbations affect physical HRQOL more than psychosocial HRQOL. Being hospitalized for exacerbations is associated with improvement in psychosocial HRQOL after exacerbations, whereas not being hospitalized is associated with deterioration.