Despite the emergence of cellular, animal, and clinical-based evidence demonstrating a link between hypoxia-inducible factor-1α (HIF-1α) and malignancy, the comprehensive assessment of HIF-1α in pan-cancer patients remains unclear, particularly regarding HIF-1α expression and its association with immune infiltration and immune checkpoint. The present study aimed to investigate the role of HIF-1α expression in various types of malignancies through bioinformatics analysis.We investigated the expression and prognostic value of HIF-1α in pan-cancer based on the TCGA (The Cancer Genome Atlas) dataset. The abundance of immune infiltration was estimated by xCell immune deconvolution methods. We investigated the relationship of HIF-1α expression with immune infiltration and immune checkpoint gene expression, with a focus on gastric adenocarcinoma (STAD) and lung squamous cell carcinoma (LUSC).HIF-1α expression had different effects on the prognosis of various cancers. In contrast to the protective effect of HIF-1α expression in LUSC, high levels of HIF-1α expression played a detrimental role in the survival of STAD patients. There was a significant positive correlation between HIF-1α expression and immune infiltration in STAD patients, including regulatory T-cells (Tregs), T-cell CD4+ Th2, neutrophils, M1 and M2 macrophages. In addition, immune checkpoint molecules showed different HIF-1α-related profiles in various carcinomas.A relatively comprehensive view of the oncogenic role of HIF-1α in various tumors based on a pan-cancer analysis is provided in this study. HIF-1α may be considered a poor prognostic biomarker for STAD and, moreover, it may be involved in regulating tumor immune infiltration.Copyright 2022, International Institute of Anticancer Research.