This study developed further clinical experience in using a single agent ("monotherapy") as empirical treatment for neutropenic patients with fever, and compared the safety and toxicity of two candidate agents, ceftazidime and ciprofloxacin. A prospective, randomized, single-center efficacy and safety comparison was conducted of intravenous ciprofloxacin, 200 mg every 12 hours, and ceftazidime, 2 g every eight hours, as initial empirical therapy in neutropenic patients with fever. Regimens were modified as necessary, guided by laboratory results and/or the clinical condition. Response was evaluated at 72 hours and at the end of the neutropenia. Toxicity was evaluated by regular clinical examination and laboratory investigations. A total of 43 patients with 51 febrile neutropenic episodes were enrolled into the study and randomly assigned to one of the two regimens. Five episodes were excluded from evaluation of efficacy because of protocol violations, leaving 46 evaluable episodes (21 ciprofloxacin, 25 ceftazidime). The two groups were well matched for risk factors for infection. There were no differences between the two groups in response rates either at 72 hours or at the end of neutropenia, although in the vast majority of patients some modification of the initial therapy was required. No patients died of uncontrolled bacterial infection. Superinfection with gram-positive cocci (often streptococci) was seen primarily in bone marrow transplant recipients who had been randomly assigned to receive ciprofloxacin. This study demonstrated that, in certain circumstances, a single antibiotic can be used successfully as initial empirical therapy in febrile neutropenic patients. In this study, ceftazidime and ciprofloxacin were generally of equal efficacy, but there appeared to be an increased incidence of streptococcal superinfection in bone marrow transplant recipients who received ciprofloxacin.