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Highlights • Gram-negative bacteremia (GNB) is a high-risk form of infection. • Elevation of IL-6 and IL-10 were associated with GNB and septic shock. • IL-6 and IL-10 are better than CRP and PCT to identify high-risk infection. Abstract The aim of this study is to systematically compare the performance of C-reactive protein (CRP), procalcitonin (PCT) and serum cytokines in identifying pediatric cancer patients with high-risk infection. A prospective observational study was performed from January 2014 through December 2016. Consecutive pediatric cancer patients who experienced febrile illness during hospitalization were enrolled. The CRP, PCT, interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-α and interferon (IFN)-γ were determined within 6 h of fever onset. A total of 3118 episodes of febrile illness were included, with 13.1% episodes documented as bloodstream infection (BSI) and 3.5% diagnosed as septic shock. Patients with BSI presented much higher levels of PCT, IL-6, IL-10 and TNF-α than patients with other types of fever and have much higher incidence of septic shock (11.2% vs. 2.3%, P < 0.001). IL-6 and IL-10 showed better performance in identifying patients with gram-negative bacteremia (GNB) and septic shock than CRP and PCT, respectively. The area under the curve (AUCs) of receiver operating characteristic (ROC) curve for septic shock prediction were 0.65, 0.78, 0.89 and 0.87 for CRP, PCT, IL-6 and IL-10, respectively. Furthermore, elevation of IL-6 and IL-10 were strongly associated with the development of GNB and septic shock. Our results indicate that BSI, especially GNB, is a high-risk form of infection which results in high incidence of septic shock. IL-6 and IL-10 performance better than CRP and PCT in identifying patients with high-risk febrile illness. [ABSTRACT FROM AUTHOR]