Our objective was to study the effect of tobramycin solution for inhalation (TSI; TOBI, Chiron Corp.) on lung function decline rate in 400 young persons with cystic fibrosis (CF) and mild lung disease. Effects on hospitalization, antibiotic use, school days missed, and nutritional status also were determined. This was an open-label, randomized (stratified by sex and age group, i.e., 6-10 and 11-15 years), parallel-group, multicenter study. Routine subject management (control group) was compared to routine management plus 28 days of twice-daily TSI inhalation, followed by 28 days off the drug (TSI group) for 56 weeks. Primary efficacy endpoints included rate of lung function decline (as measured by forced expiratory volume in 1 sec; FEV(1)), hospitalization, and concomitant antibiotic use. Safety was assessed by analysis of treatment-emergent adverse events. Only 184 of 400 planned subjects were recruited and randomized (93 to the TSI group, and 91 to the control group). Enrollment was ended after 2 years because of difficult recruitment. An interim safety review showed a 2.42-fold risk of respiratory hospitalization for control group subjects (P = 0.020), and the study was terminated. Sixty-three subjects (34.2%) completed the entire study (30 in the TSI group, or 32.3%; and 33 in the control group, or 36.3%). Significantly fewer TSI subjects were hospitalized for worsening of respiratory symptoms (11.0% vs. 25.6%; P = 0.011), and fewer TSI subjects were hospitalized overall (16.5% vs. 27.8%; P = 0.065). Fewer TSI subjects received antibiotics other than the study drug (78.0% vs. 95.6%), and significantly fewer received oral antibiotics (76.9% vs. 91.1%; P = 0.009). No other safety or adverse event differences were observed. In conclusion, significant reductions in respiratory hospitalizations, concomitant antibiotic use, and a trend towards improvement in percent predicted forced expiratory flow (FEF(25-75)) provide evidence of a clinical benefit of TSI use in young persons with CF and mild lung disease. An effect on lung function decline rate could not be evaluated as planned, due to inadequate enrollment and early study termination.