To evaluate whether increased airway reactivity affected the course of patients with cystic fibrosis (CF), we categorized 40 CF patients as to methacholine sensitivity and then evaluated their disease activity and natural history. Twenty methacholine reactors had more severe lung disease (lower S-K clinical scores and more impairment of pulmonary function) than did 16 nonreactive patients, and acute bronchodilator response was greater in the methacholine reactors. Thirty-four patients were followed prospectively over a 17- to 24-month period. Among 19 methacholine reactors, there were more pulmonary exacerbations and a more rapid decline in FEV1. In general, increased obstruction was associated with increased reactivity. Although the data are subject to differing interpretations, they are consistent with the hypothesis that in patients with CF, airway hyperreactivity occurs secondary to bronchial damage, age, is associated with more rapid pulmonary deterioration, and is an unfavorable prognostic finding.