The aim of this study was to investigate changes in serum cytokine levels in children with handfoot- and-mouth disease (HFMD) and their clinical significance. Clinical data from 241 children with HFMD, hospitalized between May 2012 and January 2013, were analyzed retrospectively. Patients were divided into a normal case group (n=107) and a severe case group (n=134), and the clinical features of the children were summarized. Concurrently, a etiological examination was performed, and the levels of 5 cytokines were measured: interleukin (IL)-2, IL-6, IL-10, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ. There was no significant difference in the age, sex ratio, length of hospital stay, and the highest temperature between groups. IL-2, IL- 6, IL-10, and TNF-α levels were significantly higher (P<0.05) in the severe case group than in the normal case group; however, there was no significant difference in IFN-γ levels between the 2 groups. Elevated cytokine levels measured in severe cases of HFMD, suggesting that cytokinerelated inflammation and anti-inflammatory responses might be involved in the development of severe HFMD.