Objectives: The aim of this study is to investigate the relationship between cytokine gene polymorphisms and Epstein–Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) in children, and to further reveal the possible mechanisms of EBV-HLH.Methods: Forty-one patients with EBV-HLH, 70 patients with infectious mononucleosis (IM), and 170 EBV-seropositive healthy children were evaluated. Gene polymorphism typing was performed by a polymerase chain reaction with a sequence-specific primer of a commercially available cytokine genotyping kit. Comparison of cytokine gene polymorphisms between EBV-HLH, IM patients, and healthy controls was analyzed statistically using Chi-square test or Fisher's exact test.Results: The frequencies of IL-10-592 C allele or IL-10-592 CC genotype were significantly higher in patients with EBV-HLH than in IM and healthy children (P < 0.001), but no significant difference was observed between IM and healthy children.Conclusion: IL-10-592 locus gene polymorphism is associated with the development of EBV-HLH in Chinese children.