Febrile neutropenia (FEN) is a leading complication of intensive chemotherapy. With this prospective randomized study, the authors aimed to compare the effectiveness of sulbactam-cefoperazone (SC) versus carbapenems, as empirical monotherapy in febrile neutropenic children with lymphoma and solid tumors. Febrile neutropenic children (age <= 16 years) hospitalized at the authors' center for lymphomas or solid tumors between March 2007 and June 2009 were included in the study. Patients randomly received SC or carbapenem. Patients were reevaluated at 72 hours and in case of persistent fever, an aminoglycoside and/or a glycopeptide was added to the antibiotic treatment. When a resistant pathogen was isolated, the antibiotic therapy was modified. Treatment responses was defined as success without modification, overall success, or failure. Two hundred and eight episodes were documented in 128 patients (F/M: 56/72), with a median age of 7 years (0.5-17.4 years). Absolute neutrophil count and duration of neutropenia in patients treated with SC and carbapenems were 133/mm(3) (0-500) and 113/mm(3) (0-500), and 4 days (1-21) and 5 days (2-20), respectively. In the SC and carbapenem groups, 82 (78.8%) and 84 episodes (80.7%) improved with treatment, whereas 21 (20.2%) and 19 (18.3%) episodes required treatment modification respectively. One patient from each treatment group died according to febrile neutropenia. The overall success rates were 99% in both groups (P = .94). Empiric SC therapy was found to be as effective as carbapenem monotherapy in pediatric febrile neutropenic patients with lymphoma and solid tumors.