Abstract Background Guidelines about febrile neutropenia in paediatric patients are not homogeneous; the best empiric treatment of this condition should be driven by local epidemiology. The Weighted-Incidence Syndromic Combination Antibiogram (WISCA) addresses the need for disease-specific local susceptibility evidence that could guide empiric antibiotic prescriptions based on outcome estimates of treatment regimens obtained as a weighted average of pathogen susceptibilities. This study developed a WISCA model to inform empirical antibiotic regimen selection for febrile neutropenia (FN) episodes in onco-haematological paediatric patients treated at two Italian paediatric tertiary centres. Methods We included blood cultures from patients with a bloodstream infection and neutropenia admitted to the Paediatric Haematology-Oncology wards in Padua and Genoa Hospitals from 2016 to 2021. WISCAs were developed by estimating the coverage of 20 antibiotics as monotherapy and of 21 combined regimens with a Bayesian probability distribution. Results We collected 350 blood cultures, including 196 g-negative and 154 g-positive bacteria. Considering the most used antibiotic combinations, such as piperacillin–tazobactam plus amikacin, the median coverage for the pool of bacteria collected in the study was 78%. When adding a glycopeptide, the median coverage increased to 89%, while the replacement of piperacillin–tazobactam with meropenem did not provide benefits. The developed WISCAs showed that no monotherapy offered an adequate coverage rate for the identified pathogens. Conclusions The application of WISCA offers the possibility of maximizing the clinical utility of microbiological surveillance data derived from large hospitals to inform the choice of the best empiric treatment while contributing to spare broad-spectrum antibiotics.