Ceftriaxone and cefoperazone monotherapy was compared in a multicentered, randomized, nonblinded, prospective study of patients with nosocomial pneumonia. These antibiotics were equally effective, with an overall successful treatment rate of 48 (80%) of 60 for the cefoperazone-treated patients and 35 (70%) of 50 for the ceftriaxone-treated patients. Patients with nursing-home-acquired pneumonia had similar bacterial pathogens and an almost identical cure rate to those patients with hospital-acquired infection. There was no statistical difference in the incidence of side effects of superinfections. The development of secondary pneumonia with resistant bacteria was low, 3% with cefoperazone and 4% with ceftriaxone. When antibiotic, administrative, and laboratory costs were calculated, cefoperazone was slightly less expensive than ceftriaxone. Both cefoperazone and ceftriaxone are effective therapy for the treatment of nosocomial pneumonia.