Cefoperazone monotherapy was compared with combination antibiotic therapy in a randomized prospective evaluation of patients with hospital-acquired pneumonia. Cefoperazone was as effective as either clindamycin/gentamicin or cefazolin/gentamicin (cure rate: 45 of 52 cefoperazone-treated patients [87 percent], versus 44 of 61 combination-therapy patients [72 percent], p = 0.069). With the exception of hypoprothrombinemia in those patients who did not receive prophylactic vitamin K, there was no difference in the incidence of side effects. In addition, no difference was noted in the incidence of superinfections or secondary pneumonias. When antibiotic costs, administration costs, and laboratory costs were considered, cefoperazone monotherapy was the least expensive antibiotic regimen. Cefoperazone is a suitable alternative to combination antibiotic therapy for the treatment of hospital-acquired pneumonia.