Objective: To investigate the expression level and clinical significance of interferon regulatory factor 6 (IRF6) in clear cell renal cell carcinoma (ccRCC), and to analyze its association with the tumor immune microenvironment. Methods: The expression of IRF6 in ccRCC tissues was analyzed using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Clinical correlation, survival analysis, Cox regression, and nomogram modeling were performed to evaluate its prognostic value. The relationship between IRF6 expression and the tumor immune microenvironment was assessed using the ESTIMATE and CIBERSORT algorithms, followed by correlation analysis with immune checkpoint molecules and tumor mutation burden (TMB). Finally, immunohistochemistry (IHC) was conducted on 30 clinical samples to validate IRF6 protein expression. Results: IRF6 expression was downregulated in ccRCC tissues compared with normal kidney tissues (P<0.001). Low IRF6 expression was associated with higher histologic grade, advanced clinical stage, and metastatic status (P<0.05). Survival analysis demonstrated that patients with low IRF6 expression had shorter overall survival (OS), disease-specific survival (DSS), and progression-free survival (PFS) (P<0.001). Multivariate Cox regression confirmed that IRF6 was an independent protective prognostic factor (P<0.01). The nomogram incorporating IRF6 exhibited good predictive performance. Low IRF6 expression was correlated with higher ImmuneScore and ESTIMATE Score, increased infiltration of macrophages (M0/M1) and activated dendritic cells (P<0.05), and showed a negative correlation with immune checkpoints such as PD-1 and CTLA-4. IRF6 expression was inversely correlated with TMB (P<0.001). IHC results revealed that IRF6 was lowly expressed in tumor tissues (P<0.05). Conclusion: IRF6 is downregulated in ccRCC and serves as an independent protective prognostic biomarker. Its low expression is associated with an immunosuppressive tumor microenvironment and reduced immunotherapy responsiveness. IRF6 may act as a promising biomarker for prognosis evaluation and prediction of immunotherapy response in ccRCC.