A controlled study was designed to clarify the indications for antibiotic therapy in children with advanced cystic fibrosis hospitalized with respiratory exacerbations. Twenty-two children with severe CF and signs of acute lower respiratory infection were randomly assigned to receive either cloxacillin or carbenicillin plus gentamicin administered intravenously for ten days. Other aspects of therapy were constant. The groups were comparable in all respects and Pseudomonas aeruginosa was the predominant sputum pathogen in most patients. Clinical improvement, chest radiograph changes, evidence of airway obstruction, and bacteriologic flora of sputum were no different regardless of the regimen used. These results suggest that the use of anti-Pseudomonas medication in these children may not always be necessary. These observations need to be confirmed by blind-controlled studies in larger numbers of patients with mild as well as severe respiratory involvement.