Objective: To explore the diagnostic effectiveness and significance of the pediatric early warning score (PEWS), in conjunction with immunoglobulin levels (IgA, IgG, IgM), in critically ill pediatric patients diagnosed with hand-foot-and-mouth disease (HFMD). Methods: A retrospective analysis was conducted on 61 children with confirmed HFMD, and they were divided into two groups: a mild case group (n=31) and a critically ill case group (n=30), based on disease severity. PEWS scores were assigned, and serum levels of IgG, IgA, and IgM were measured for all participants. The difference of immunoglobulin levels between mild and critical children were compared, and the efficacy of separate and combined tests of PEWS and immunoglobulin levels in the diagnosis of HFMD children were analyzed by ROC curve. Results: At the time of enrollment, the consciousness, cardiovascular system, respiratory system and the total score of PEWS in the critical ill case group were higher than those in the mild case group (P<0.05). The levels of serum IgG and IgA in critical ill case group were lower than those in mild case group (P<0.05), and the level of serum IgM was higher than that in mild case group (P<0.05). ROC curve analysis showed that the area under the curve (AUC) of PEWS score, IgG, IgA, IgM, and their combined diagnosis in HFMD children were 0.735, 0.684, 0.647, 0.908, and 0.927, respectively, with the highest AUC observed in the combined detection (P<0.05). Conclusion: The PEWS score and immunoglobulin IgG, IgA and IgM levels in HFMD children changed significantly, which are closely related to the severity of the disease. Joint monitoring of PEWS score and immunoglobulin level is helpful to predict the severity of HFMD children.