Objectives: The aim of the study was to investigate the diagnostic efficacy of C-reactive protein (CRP) in predicting serious bacterial infection (SBI) in febrile children aged 3 to 36 months with extreme leukocytosis (EL), defined as a peripheral white blood cell count of 25,000 to 49,999/mm3. Methods: The presence of SBI was reviewed in previously healthy children aged 3 to 36 months with a fever of 39°C or higher and EL, who visited a tertiary care hospital emergency department between September 2010 and August 2015. We measured cutoff values of CRP with corresponding likelihood ratios (LRs) and posttest probabilities (PPs). Results: Of 9989 febrile children, 4252 (42.6%) underwent assays for white blood cell and CRP. Of 233 (5.5%) children with EL, 133 (3.1%) were enrolled, of whom 43 (32.3%; 95% confidence interval [CI], 25.0%–40.7%) had SBI, including 33 pyelonephritis, 5 deep abscesses, 3 lobar pneumonia, and 2 soft tissue infections. With the cutoff of 7.8 mg/dL, the sensitivity of CRP in predicting SBI was 81.4% (95% CI, 67.4%–90.3%); the specificity, 80.0% (95% CI, 70.6%–87.0%); the positive predictive value, 66.0% (95% CI, 52.6%–77.3%); the negative predictive value, 90.0% (95% CI, 81.5%–94.9%); the positive LR, 4.1; and the PP, 66.0% (95% CI, 55.6%–75.0%). A CRP concentration of 16.1 mg/dL or higher yielded an LR of 11.2 and a PP of 84.2% (95% CI, 62.1%–94.5%). A CRP concentration of lower than 3.4 mg/dL yielded an LR of 0.05 and a PP of 2.4% (95% CI, 0.3%–14.6%). Conclusions: High concentration of CRP is strongly associated with the presence of SBI in febrile children with EL.