The area under the curve values of the two indexes were 0.906 and 0.897 respectively for the identification of M-HLH in the critically ill children, with CD38+/HLA-DR + CD8+ T cells% > 39.66% and IFN-γ > 22.58 exhibiting the best performance.<h4>Conclusion</h4>Cytotoxic T-cell activation profile with CD38 + HLA-DR + CD8+ T cells% and IFN-γ is valuable in the early diagnosis of HLH in critically ill children with malignancies.<h4>Impact</h4>The early diagnosis of hemophagocytic lymphohistiocytosis in critically ill children with malignancies (M-HLH) remains a major challenge for intensivists. Here, CD8A is linked to hemophagocytic syndrome.