<p>Epstein–Barr virus (EBV)-related hemophagocytic lymphohistiocytosis (EBV-HLH) and infectious mononucleosis (IM) are characterized by fever, hepatomegaly, and splenomegaly, but HLH has a 50% lethality rate. Therefore, this study aimed to compare the laboratory findings in differentiating EBV-HLH children from IM children who have fever, hepatomegaly, or splenomegaly. A total of 131 IM patients and 29 EBV-HLH pediatric patients with fever, hepatomegaly, or splenomegaly were enrolled in our study. The clinical traits and laboratory findings were analyzed, and a predictive regression analysis was also performed. EBV-HLH patients had a lower set of diagnostic markers, which included fibrinogen (FIB), white blood cells (WBC), hemoglobin (Hb), and platelet (PLT), compared to IM patients. Triglyceride (TG) and ferritin were elevated obviously in EBV-HLH patients compared to IM patients. CD4^dimCD8⁺ T cells are highly activated T cells. EBV-HLH patients experienced a significant decrease in the absolute number and ratio of CD4^dimCD8⁺T cells (CD4^dimCD8⁺T#, CD4^dimCD8⁺T%) compared to IM patients in our study. The AUC of CD4^dimCD8⁺ T # in the diagnosis of EBV-HLH was 0.920 with a sensitivity of 86.2% and a specificity of 90.1%. A logistic regression analysis was developed to improve sensitivity. The results revealed that lower levels of Hb, FIB, and CD4^dimCD8⁺T cells were risk factors for EBV-HLH. The regression model for separating EBV-HLH from EBV-IM had an AUC of was 0.996 with a sensitivity of 100% and a specificity of 95.3%. The ratio and absolute number of CD4^dimCD8⁺T cells were decreased in IM and EBV-HLH patients. EBV-HLH can be identified in IM patients with fever, hepatomegaly, or splenomegaly by detecting Hb, FIB, and the absolute number of CD4^dimCD8⁺T cells.</p>