Background: Despite numerous treatments available, clear cell renal cell carcinoma (ccRCC) remains a deadly and invasive cancer. Anoikis-related genes (ARGs) are essential regulators of tumor metastasis and development. However, the potential roles of ARGs in ccRCC remain unclear. Methods: Based on the TCGA-KIRC cohort and GeneCards database, we identified differentially expressed ARGs in ccRCC. Then a 4 ARGs risk model was created by Cox regression and LASSO. The Kaplan-Meier and receiver operating characteristic (ROC) curves were utilized to verify the predictive efficacy of the prognostic signature. Subsequently, the possible molecular mechanism of ARGs was investigated by functional enrichment analysis. To assess the immune infiltration, immune checkpoint genes, and immune function in various risk groups, single sample gene set enrichment (ssGSEA) algorithm was employed. Furthermore, the low-risk and high-risk groups were compared in terms of tumor mutation burden (TMB). Ultimately, we analyzed the protein expression of these four ARGs utilizing the western blot test. Results: Four genes were utilized to create a risk signature that may predict prognosis, enabling the classification of KIRC patients into groups with low or high risk. The reliability of the signature was examined utilizing survival analysis and ROC analysis. According to the multivariate Cox regression result, the risk score was a reliable independent prognostic predictor for KIRC patients. The novel risk model could differentiate between KIRC patients with various clinical outcomes and represent KIRC's specific immune status. An analysis of the correlation of TMB and risk score indicated a positive correlation between them, with high TMB being potentially linked to worse outcomes. Conclusion: Based on our findings, the prognostic signature of ARGs may be employed as an independent prognostic factor for ccRCC patients. It may introduce alternative perspectives on prognosis evaluation and serve as a prominent reference for personalized and precise therapy in KIRC.