Abstract: Objective: To investigate the impact of copper metabolism-related gene cytochrome c oxidase copper chaperone 17 (COX17) on the occurrence, development and prognosis of head and neck squamous cell carcinoma (HNSCC). Methods: Bioinformatics analysis was employed to assess the expression differences of COX17 between HNSCC and normal tissues. Nomogram was generated to verify the role of COX17 in predicting the prognosis of HNSCC. Functional enrichment analysis of COX17-related genes was conducted using KEGG and GO analyses, and the relationship between COX17 expression and the abundance immune cell infiltration in HNSCC tissues was analyzed using ssGSEA. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was utilized to verify the expression differences of COX17 between HNSCC cell lines and immortalized normal epithelial cell lines. The effect of COX17 on cell proliferation and invasion was assessed using the cell counting kit-8 (CCK-8) assay and Transwell experiments, respectively. Results: COX17 expression was significantly up-regulated in HNSCC (P＜0.05). Prognostic analysis indicated that COX17 expression was closely associated with the overall survival (OS) of HNSCC patients (P＜0.05). Immune infiltration correlation analysis revealed a significant negative correlation between COX17 expression and the abundance of various immune cell infiltration (all P＜0.001). Knocking down COX17 significantly inhibited the proliferation and invasion abilities of HNSCC cell line SCC-9 and SAS. Conclusion: The expression of COX17 can affect the proliferation and invasion of HNSCC cells and is potentially associated with immune cell infiltration in HNSCC tissues. As a biomarker of mitochondrial copper metabolism, COX17 may be an effective indicator for assessing the prognosis of HNSCC and a potential therapeutic target.