BACKGROUND H2A histone family member Z (H2AFZ) is a special subtype in the H2A histone family, which participates in the regulation of gene transcription. Nevertheless, little is known about the role of H2AFZ in the tumor microenvironment and genetic factors associated with lung cancer. MATERIAL AND METHODS The expression of H2AFZ in LUAD was analyzed via Tumor Immune Estimation Resource (TIMER), the Cancer Genome Atlas (TCGA), and Gene Expression Omnibus (GEO) databases at the mRNA level. To detect the protein expression level of H2AFZ, immunohistochemistry (IHC) was performed using LUAD tissues and non-tumor lung tissues. Kaplan-Meier survival analysis and Cox regression analysis were conducted to identify the effect of H2AFZ expression on overall survival (OS) based on TCGA-LUAD and the GEO dataset GSE68465 cohorts, and our LUAD patient cohort was used for validation. Identification of signaling pathways associated with the expression of H2AFZ was performed using Gene Set Enrichment Analysis (GSEA). The influences of expression of H2AFZ on tumor immune-infiltrating cell (TIICs) were assessed via TIMER and CIBERSORT. RESULTS The expression of H2AFZ was increased in LUAD tissues at both mRNA and protein levels. In addition, high expression of H2AFZ predicted poor OS and might be an independent prognostic predictor in LUAD patients. Moreover, H2AFZ affected the relative proportion of TIICs and was positively associated with Myeloid-derived suppressor cells (MDSC) infiltration level in LUAD. CONCLUSIONS H2AFZ was upregulated in LUAD and related to poor prognosis of LUAD patients; thus, it could be an underlying prognostic biomarker correlated with immune infiltration in LUAD.