Management of febrile pediatric patients with cancer with an absolute neutrophil count of 500/µL or greater is unclear. The Esbenshade Vanderbilt (EsVan) risk prediction models have been shown to predict bloodstream infection (BSI) likelihood in this population, and this study sought to prospectively validate and implement these models in clinical practice.Data were prospectively collected on febrile pediatric patients with cancer with a central venous catheter from April 2015 to August 2019 at a single site, at which the models (EsVan: 2015 to 2017; EsVan2: October 2017 to 2019) were initially developed and subsequently implemented for clinical management in well-appearing nonseverely neutropenic individuals. It was recommended that patients with low BSI risk (< 10%) be discharged home without antibiotics, those with intermediate BSI risk (10%-39.9%) be administered an antibiotic before discharge, and those with high BSI risk (> 40%) be admitted on broad-spectrum antibiotics. Seven-day outcomes were then collected and EsVan models were prospectively validated and C-statistics estimated.In 937 febrile, nonsevere neutropenia episodes, frequencies of low-, intermediate-, and high-risk episodes were 88.9%, 8.6%, and 2.3% respectively. BSI incidence was 4.2% (39 of 937). Within risk groups, low-risk BSI incidence was 1.9% (16 of 834) with BSI incidence of 13.6% and 54.5% for intermediate- and high-risk episodes, respectively. Empirical intravenous antibiotics were administered in 21.1% of low-risk episodes at presentation and at 7 days postpresentation, 72.3% of episodes never required intravenous antibiotics. There were no deaths or clinical decompensations attributable to antibiotic delay. For BSI detection, EsVan and EsVan2 models applied to the new cohort achieved C-statistics of 0.802 and 0.824, respectively.Prospective, real-time clinical utilization of the EsVan models accurately predicts BSI risk and safely reduces unnecessary antibiotic use in febrile, nonseverely neutropenic pediatric patients with cancer.