Left-sided endocarditis caused by Pseudomonas aeruginosa is frequently associated with failure of medical therapy in man. The efficacy of ciprofloxacin and netilmicin + azlocillin has been studied in 79 rabbits with aortic valve endocarditis caused by a serum-resistant strain of P. aeruginosa. Infected animals received either: no therapy; ciprofloxacin (80 mg/kg/day); or netilmicin (6.5 mg/kg/day) + azlocillin (400 mg/kg/day). Ciprofloxacin significantly lowered vegetation titers of P. aeruginosa at days 6 and 10 of therapy compared with netilmicin + azlocillin (P less than 0.001). Similarly, ciprofloxacin was significantly more effective in sterilizing vegetations (P less than 0.005), curing P. aeruginosa endocarditis (P less than 0.001), and preventing bacteriological relapse after discontinuing antibiotic therapy (P less than 0.005). Both antibiotic regimens were equally effective in sterilizing renal abscesses. Resistance to azlocillin was occasionally observed in vivo among P. aeruginosa isolates within cardiac vegetations during the second week of therapy, but not to ciprofloxacin or netilmicin.