BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cell carcinoma. The myosin 6 (MYO6) plays an important role in tumorigenesis and progression. However, its prognostic and immunological effects in ccRCC have not been comprehensively and systematically studied. Therefore, this study aimed to investigate the prognostic value and immune-related role of MYO6 in ccRCC. METHODS: The expression of MYO6 mRNA and protein in normal and tumor tissues using The Cancer Genome Atlas (TCGA) and other public databases were analyzed. In order to further improve the accuracy of the results, immunohistochemistry (IHC) was performed to verify the results. R software, an integrated repository portal for tumor-immune system interactions (TISIDB) and other online analysis tools were used to investigate the relationship between MYO6 expression and clinicopathological features, diagnostic and prognostic value, and the level of immune infiltration in patients with ccRCC. MYO6 genomic alterations were then investigated using the cBio Cancer Genomics Portal (cBioPortal) database. Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and Gene Set Enrichment Analysis (GSEA) enrichment analysis were used to elucidate the biological processes and signaling pathways. Finally, a protein interaction network was constructed using Biological Universal Repository for Interactive Datasets (BioGRID) and some online analysis tools to investigate the correlation between MYO6 and its co-expressed genes in ccRCC patients. RESULTS: In the present study, MYO6 expression was significantly reduced in ccRCC tumors compared with normal tissues.This was consistent with the results of immunohistochemistry. Lower MYO6 expression levels were significantly associated with higher cancer grade and later TNM stage in ccRCC. Compared with the MYO6 high expression group, ccRCC patients with low MYO6 expression had a poor prognosis of overall survival (OS). MYO6 expression has diagnostic and prognostic potential in ccRCC. MYO6 expression is associated with different tumor-infiltrating immune cells, especially macrophages. CONCLUSIONS: The findings suggest that reduced MYO6 expression levels are associated with disease progression, poor prognosis, and immune cell infiltration, and can be considered as a promising prognostic biomarker for ccRCC.