With larger numbers of adult patients with cystic fibrosis (CF) in the workplace, the issue of disability has arisen increasingly. We examined relationships between measures of pulmonary impairment and work/school capability and then determined whether quantification of aerobic fitness improved predictability of disease-related disability. We studied 73 patients with CF who performed lung function and exercise capacity tests, completed a work/education questionnaire, and were scored for clinical and chest radiographic status. Patients who were characterized as unemployed and in poor health had more severe pulmonary disease according to American Thoracic Society impairment/disability criteria. Subjects were further classified into three groups based on employment or education status over the preceding 12 months. FEV1, maximal oxygen consumption, Schwachman-Kulczycki clinical and Brasfield radiographic scores, and frequency of pulmonary exacerbations over 2 years were associated with disability, but change in FEV1 over 2 years and oxygen saturation at rest or exertion were not. FEV1 and Schwachman-Kulczycki scores were the best independent predictors of impairment/disability; specific thresholds used in other pulmonary diseases were of limited utility. We conclude that after accounting for either current level of FEV1 or Schwachman-Kulczycki scores, no other physiological or clinical measures contribute to predicting limitation in a work or school environment.