To determine the frequency of respiratory syncytial virus (RSV) as the cause of hospitalization for acute pulmonary exacerbations in young infants with cystic fibrosis (CF), and to assess the clinical effects of RSV infections, we prospectively followed 48 children with a diagnosis of CF after identification by newborn screening. At a mean follow-up age of 28.8 months (range 5 to 59), 18 infants (38%) had been hospitalized a total of 30 times for acute respiratory distress. At the time of admission, 18 infants (60%) were less than 12 months, 8 (27%) between 12 and 24 months, and 4 more than 2 years of age. The RSV was identified in seven hospitalized infants, as determined by fluorescent antibody, immunoassay, or culture. Before admission with RSV infection, one of the seven infants had chronic respiratory signs, none had Brasfield chest x-ray scores below 20, and a previous throat culture was positive for Staphylococcus aureus in one infant. Hospitalizations were prolonged (mean duration 22 days), and were characterized by significant morbidity, with three infants (43%) requiring mechanical ventilation and five infants (71%) requiring home oxygen therapy for persistent hypoxemia at discharge. At a mean follow-up age of 26 months, these infants more frequently have chronic respiratory signs (p<0.01) and lower chest radiograph scores (p<0.05) than other CF infants. These findings demonstrate that RSV is an important cause of early acute respiratory tract morbidity in young infants with CF, and suggest the need for studying new strategies to implement early and aggressive antiviral therapy in young infants with CF.