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Background and purpose: Systemic upregulation of inflammatory cytokines is characteristic of critical severe hand, foot, and mouth disease (HFMD) with pulmonary edema. Thus, immunomodulatory medicines such as steroids, including methylprednisolone, have been proposed to treat patients with severe HFMD in China, because it is postulated that inflammatory cytokines play a role in the development of severe complications. This study is to further investigate the inflammatory response in the relatively mild HFMD patients, and whether steroid treatment has a beneficial effect on the suppression of inflammation in HFMD patients. Method: We measured the levels of 50 kinds of chemokines, cytokines, growth factors and soluble receptors in serum samples from control patients without HFMD and the HFMD patients with or without prior treatment of intravenous methylprednisolone. Results: Our present study found that even relatively mild HFMD patients without central nervous system (CNS) complications had elevated serum levels of inflammatory cytokines, including interleukin (IL)-3, IL-6, IL-12p40, and tumor necrosis factor (TNF)-α, which suggested systemic inflammation. In contrast, these patients also have decreased levels of other serum biomarkers, including IL-1Ra, IL-8, IL-16, soluble ICAM-1, CXCL-1, and CCL27. The dysregulation of cytokine and chemokine expression may be involved in CNS complications and unbalanced circulating leukocytes in HFMD patients. Surprisingly, patients treated with methylprednisolone had no difference in the expression levels of HFMD-associated biomarkers instead had slightly increased levels of IL-17A, which was not associated with the occurrence of HFMD. Conclusion: Whether steroid treatment has any beneficial effect on the prognosis of HFMD patients requires to be further investigated. Author Summary: Systemic inflammation is characteristic of severe hand, foot, and mouth disease (HFMD). Steroids are considered immunomodulators and have been officially recommended to treat the severe HFMD patients with CNS complications in China. So far, it is uncertain whether steroid treatment has an immunomodulatory role in inflammation in HFMD patients and has a real beneficial effect on their prognosis. This study revealed that even relatively mild HFMD patients without CNS complications had elevated inflammation. Unexpectedly, the inflammatory cytokine levels in patients treated with methylprednisolone, one kind of steroid, were not significantly different from those in patients without the treatment. Rather, the treated patients tended to have elevated levels of IL-17A, whose expression levels were actually not significantly associated with the presence of HFMD. IL-17A is known to play a role in the pathogenesis of CNS-related inflammatory diseases. Altogether, our study does not support the presumption that steroids have beneficial effect on the prognosis of HFMD patients by inhibiting systemic inflammation. [ABSTRACT FROM AUTHOR]