Treatment of episodes of fever and neutropenia in pediatric hematology-oncology patients includes hospitalization and administration of intravenous antibiotics until the patient is afebrile and no longer neutropenic. The present analysis characterizes retrospectively febrile episodes in neutropenic pediatric hematology-oncology patients with regard to frequency of documented infections, organisms associated with these infections, efficacy of a standardized antibiotic regimen, and safety of early antibiotic discontinuation under defined conditions. A total of 149 pediatric febrile neutropenic episodes were identified during a 4-year period between 1990 and 1994. These occurred in 47 male and 19 female patients, of a mean age of 7.6 years (range 0.5-15). The most frequent diagnoses were leukemia (41% of patients), lymphoma (21%), rhabdomyosarcoma (7%), soft tissue sarcoma (5%), Ewing's sarcoma (5%), and osteosarcoma (4%). Infection was certain in 36% of febrile episodes, probable in 14%, and not determined in 50%. Patients with severe neutropenia (absolute neutrophil count < 100) had a slightly, although not significantly higher incidence of documented and probable infection (57%). Patients with solid tumor had documented infection in 40% of their febrile episodes, and the detection rate in the children with leukemia was 31% (P < .20) Blood cultures were positive in 21 (14%) of 149 episodes. Staphylococci (both coagulase-negative and coagulase-positive strains) and Pseudomonas were the organisms most frequently isolated (six episodes each). Mouth and throat (11), lungs (10), and skin (10) were the next most frequent sites of localized infection. Initial treatment consisted of piperacillin and amikacin or of vancomycin and amikacin when the source of fever was thought to be an infected central line catheter, with addition of amphotericin B by the seventh day of treatment when fever with neutropenia persisted or upon clinical suspicion of underlying fungal infection. There was a single fatality, of a patient with Burkitt's lymphoma. Antibiotics were discontinued when initial blood cultures had no growth after at least 48 hours and no source of infection was found, the blood count was improving, and if the patient became afebrile and clinically well. No patient needed readmission during the fortnight that followed discontinuation of antimicrobial therapy. Patients with negative blood cultures under defined conditions, as described above, could safely be discharged early, thus shortening the duration of intravenous antibiotic therapy and hospital stay.