We evaluated patients with cystic fibrosis (CF) and moderate obstructive lung disease in pulmonary exacerbation in a double-blind placebo-controlled trial to determine the contribution of antibiotic-mediated reduction in sputum bacterial density to clinical improvement. For the first 4 days of study, all patients received bronchodilating aerosols and chest physiotherapy but no antibiotics. During this time, the patients showed significant improvement in mean FVC, FEV1, and maximal midexpiratory flow rate (FEF25-75). In 12 of 13 trials, the patients showed no significant increases in the density of Pseudomonas aeruginosa during these first 4 days. In these 12 trials, the patients were stratified by their initial FVC and randomized to receive either parenteral tobramycin and ticarcillin (n = 7) or placebo (n = 5), in addition to continued aerosol and chest physiotherapy. In the remaining trial, the patient had a significant rise in density of P. aeruginosa and was assigned to the antibiotic group. During the next 14 days of therapy, the antibiotic group showed significantly (p < 0.01) greater reductions in log10 colony-forming units (cfu) of P. aeruginosa per gram of sputum and greater increases in FVC, FEV1, and FEV25-75 than did the placebo group. The degree of decrease in log10 cfu P. aeruginosa/g sputum correlated significantly (p < 0.001) with the degree of improvement in FVC, FEV1, and FEF25-75. Moreover, significantly (p < 0.01) more patients in the antibiotic group achieved better than a 2 log10 reduction in cfu P. aeruginosa/g of sputum, a 10% increase in FVC, a 20% increase in FEV1, and a 30% increase in FEF25-75 than did those in the placebo group. These results show that appropriate antibiotic therapy provides significant additional benefit to bronchodilators and chest physiotherapy in patients with CF, pulmonary exacerbation, and P. aeruginosa in their sputums. Moreover, the degree of improvement correlates with the degree of reduction of P. aeruginosa and total bacterial density in the sputum.