The objective of this study was to compare the effectiveness of piperacillin-tazobactam(PIP/TAZO) plus amikacin (AMK) (PIP/TAZO+AMK) versus cefoperazone-sulbactam (CS) plus AMK (CS+AMK) for the treatment of febrile neutropenia (FN) in children with cancer. The study was designed prospectively and randomized in 0- to 18-year-old children with lymphoma or solid tumor who were hospitalized with FN diagnosis. Consecutively randomized patients received either PIP/TAZO 360 mg/kg/day in 4 doses plus AMK 15 mg/kg/day in 3 doses or CS 100 mg/kg/day in 3 doses plus AMK 15 mg/kg/day in 3 doses intravenously. Treatment modification was defined as any change in the initial empirical antibiotic therapy. A total of 116 FN episodes were managed in 46 patients (26 boys and 20 girls) with a median age of 6.5 years (range .8-17.0) during the study period. Success rates without modification of therapy were 47.5% and 52.6% in PIP/TAZO+AMK group and CS+AMK group, respectively (P>.05). No statistical difference was found between treatment groups in terms of durations of neutropenia, fever, and hospitalization. The overall success rate in all groups was 97.4%. No major side effect was observed in either group during the course of the study. Our study is the first to compare the effectiveness of PIP/TAZO+AMK and CS+AMK therapies. Both combinations were effective and safe as empirical therapy for febrile neutropenic patients.