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Severe drug eruption (SDE), a common skin disease, becomes dangerous when it occurs in patients with human immunodeficiency virus (HIV). However, the molecular mechanisms are poorly understood. Forty patients including HIV+ SDE+ (n = 15), HIV− SDE+ (n = 15) and HIV+ SDE− (n = 10) subjects were enrolled in our study. All HIV+ patients were at acquired immune deficiency syndrome (AIDS) stage. Serum levels of TNF‐α, IFN‐γ, IL‐4, IL‐13, IL‐6, CXCL9, and CCL17 were quantified by ELISA. Epstein–Barr virus (EBV) and cytomegalovirus (CMV) loads were quantified by RT‐qPCR. CD4, CD8, Th1, Th2, TNF‐α‐CD8, and IFN‐γ‐CD8 T cell populations were measured by flow cytometry. Levels of biochemical indexes in HIV+ SDE+ patients were significantly different from in HIV− SDE+ patients (P <.05). EBV and CMV viral loads were significantly higher in HIV+ SDE+ patients, but not in HIV− SDE+ patients (P <.05). Inflammatory cytokines TNF‐α and IFN‐γ were significantly elevated in HIV+ SDE+ patients (P <.05). Th2/Th1 populations and TNF‐α secreting or IFN‐γ secreting CD8+ T cells, were significantly up‐regulated in HIV+ SDE+ patients compared to HIV− SDE+ patients (P <.05). Conversely, the CD4/CD8 ratio was significantly down‐regulated in HIV+ SDE+ patients compared to HIV− SDE+ patients (P <.05). HIV infection confers distinct clinical phenotypes and immune inflammatory mechanisms in SDE. Sustained EBV and CMV activation, unbalanced Th2/Th1 and overactive CD8+ T cells mediating a pro‐inflammatory response could act as distinct mechanisms in the aggravation of SDE in HIV+ SDE+ patients. [ABSTRACT FROM AUTHOR]