Objective To determine whether updating a diagnostic prediction model by adding a combination assay (tumour necrosis factor-related apoptosis-inducing ligand, interferon γinduced protein-10 and C reactive protein (CRP)) can accurately identify children with pneumonia or other serious bacterial infections (SBIs). Design Observational double-blind diagnostic study. Setting Two hospitals in Israel and four hospitals in the Netherlands. Patients 591 children, aged 1-60 months, presenting with lower respiratory tract infections or fever without source. 96 of them had SBIs. The original Feverkidstool, a polytomous logistic regression model including clinical variables and CRP, was recalibrated and thereafter updated by using the assay. Main outcome measures Pneumonia, other SBIs or no SBI. Results The recalibrated original Feverkidstool discriminated well between SBIs and viral infections, with a c-statistic for pneumonia of 0.84 (95% CI 0.77 to 0.92) and 0.82 (95% CI 0.77 to 0.86) for other SBIs. The discriminatory ability increased when CRP was replaced by the combination assay; c-statistic for pneumonia increased to 0.89 (95% CI 0.82 to 0.96) and for other SBIs to 0.91 (95% CI 0.87 to 0.94). This updated Feverkidstool improved diagnosis of SBIs mainly in children with low-moderate risk estimates of SBIs. Conclusion We improved the diagnostic accuracy of the Feverkidstool by replacing CRP with a combination assay to predict pneumonia or other SBIs in febrile children. The updated Feverkidstool has the largest potential to rule out bacterial infections and thus to decrease unnecessary antibiotic prescription in children with low-to-moderate predicted risk of SBIs.