The long-term efficacy and safety of aminoglycoside aerosol therapy for Pseudomonas aeruginosa colonization/infection in cystic fibrosis has not been fully investigated. In the present study, 14 patients with cystic fibrosis, ages 8-19 years (mean: 13.3 years), received tobramycin aerosol therapy for a mean duration of 20 months. Eighty milligrams of a tobramycin solution were inhaled twice daily after physiotherapy via a jet nebulizer. After 1 year, weight for height increased significantly by 2.9% of the predicted normal, and the Kraemer clinical score increased by 2.1 points (P less than 0.05). The frequency of hospital admissions decreased from 2.0 to 1.3 per patient, respectively, during the years before and after the study onset. The antibody response to P. aeruginosa elastase, exotoxin A, and alkaline phosphatase showed a reduction in serum titers against one or more enzymes in eight patients. The best long-term results after 12-38 months of treatment were obtained in moderately ill children. No evidence of ototoxicity or renal damage was observed. Although intermittent bacterial resistance occurred in five patients after 10-21 months of tobramycin inhalation, this was not associated with clinical deterioration. The study demonstrates the safety and clinical efficacy of long-term tobramycin aerosol therapy. Double-blind studies with larger patient cohorts are required to determine the value of aminoglycoside inhalation as an adjunct to the established therapeutic regimens.