The therapeutic activity of ciprofloxacin, enoxacin, and ofloxacin was evaluated in guinea pigs with acute and chronic experimental Pseudomonas aeruginosa pneumonia. Intratracheal instillations of P. aeruginosa resulted in fatal pneumonia in all untreated animals within 36 h. Among treatment groups (80 mg/kg [body weight] per day), cumulative survival rates were: 47%, ciprofloxacin; 55%, enoxacin; and 42%, ofloxacin. These rates were not significantly different. Intrapulmonary killing of P. aeruginosa was equivalent 3 h after a single dose of ciprofloxacin or ofloxacin (20 mg/kg) or enoxacin (40 mg/kg). The combination of ciprofloxacin with azlocillin, ceftazidime, or tobramycin did not increase the efficacy of intrapulmonary killing of P. aeruginosa over that of ciprofloxacin alone. A chronic, nonfatal bronchopneumonia was induced in guinea pigs by intratracheal instillation of microscopic agar beads impregnated with a mucoid strain of P. aeruginosa. Compared with no treatment, ciprofloxacin and enoxacin produced greater than or equal to 99.9% intrapulmonary killing, and ofloxacin sterilized the lungs completely, after 4 days of treatment. In no quinolone-treated animal did resistant strains of P. aeruginosa emerge during 4-day treatment periods. In further studies with the chronic model, oral and parenteral ciprofloxacin treatment were found to be equivalent in efficacy. We conclude that several quinolone derivatives may be effective for the treatment of P. aeruginosa pneumonia and that combinations of quinolones with beta-lactams or aminoglycosides may not increase efficacy against P. aeruginosa pneumonia.