Early recognition and distinction of Kawasaki disease (KD) from other febrile infectious diseases is one of the biggest challenges in pediatric emergency departments (PED). The aim of this study was to assess the utility of clinical findings and routinely used laboratory parameters for early discrimination between KD, invasive pneumococcal disease (IPD) and adenovirosis (AdV). A retrospective, cross-sectional study of children aged 3–36 months consecutively admitted to the PED and diagnosed with either KD (n = 110), AdV (n = 440) or IPD (n = 122) was conducted. At first presentation to the PED, 56.3% of KD patients had none or only one clinical criterion, 31% of patients with AdV and 11% with IPD had > 2 criteria. The levels of platelets (Plt), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were higher and white blood cells (WBC) significantly lower in KD than in IPD and AdV group. The WBC < 20 ×109/l showed a sensitivity of 80.9% and specificity of 79.7% in comparison to AdV. The ROC curve showed a significant, but low sensitivity for AST, ALT and Plt. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) did not show any significant diagnostic accuracy. Significant association between incomplete KD and rash, WBC < 20 ×109 and Plt > 400 ×109/L compared to AdV and conjuctivitis, rash and Plt > 400 × 109/L, was found. Due to the time delay and nonspecific early presentation, differentiating KD from IPD and AdV is challenging. Tools used for identification of patients at risk for severe bacterial infections in PED lack sensitivity for identification of KD cases. New biomarkers are warranted for distinction of KD from IPD or AdV.