In a two-year prospective study, we examined the effect of respiratory viral infections on pulmonary function in 49 patients with cystic fibrosis (mean age, 13.7 years). Nineteen normal siblings (mean age, 14) served as controls. Subjects were assessed quarterly and at the time of any respiratory illness. Each assessment included nasal washes for viral isolation and blood drawing for respiratory viral serologic studies. Pulmonary-function tests were performed at least twice yearly. Respiratory illnesses were reported significantly more often in the patients (3.7 per year) than in the normal siblings (1.7 per year), although the frequency of proved viral infections (1.67 per year) was identical. In the patients with cystic fibrosis significant correlations (P less than 0.0001) were found between the annual incidence of viral infections and every measure of disease progression in the two-year period, including the rate of decline of the Shwachman score (r = 0.71), the percentage of ideal weight for height (r = 0.80), the forced vital capacity (r = 0.85), the forced expiratory volume in the first second (r = 0.84), the forced midexpiratory flow rate (r = 0.68), and the frequency (r = 0.53) and duration (r = 0.84) of hospitalizations for respiratory exacerbations. We conclude that frequency of viral respiratory infections is closely associated with pulmonary deterioration in patients with cystic fibrosis.