Aldehyde dehydrogenase 2 (ALDH2) point mutation ALDH2*2 is the common frequent human gene variant, espically in East Asians. However, nothing is known about their expression and mechanism of action in HNSC. This research tried to explore the clinical significance and immune characteristics of ALDH2 in HNSC. The receiver operating characteristic (ROC) curve was analysed to assessment the diagnostic value of ALDH2 expression. ALDH2 expression in normal tissues and HNSC tissues were evaluated by IHC. Also we analyzed ALDH2 gene expression in 4 HNSC cell lines. ALDH2 expression was significantly reduced in HNSC tissues (p< 0.05). HNSC patients with highly expressed ALDH2 have a better prognosis (p< 0.05). Then, GSEA analysis result pointed that these gene sets were connected with signaling pathways including JAK-STAT signaling pathway. We unexpectedly found a significant prognostic effect of ALDH2 in alcohol consumption and male HNSC patients. The correlation between ALDH2 expression and immunoinhibitors showed a effect for ALDH2 in modifying tumor immunology in HNSC and there may be a possible mechanism by which ALDH2 regulates functions of T cell in HNSC. We developed a nomogram prognostic model for HNSC patients. Moreover, low ALDH2 expression was a poor prognostic factor in male alcoholics of HNSC.