OBJECTIVE: predict the relationship between EPAS-1 in the occurrence and development of renal cell carcinoma and its effect on prognosis. METHODS: The immunohistochemical EnVision two-step method was used to detect the expression of EPAS-1 protein in 145 cases of renal cell carcinoma and adjacent tissues to verify the correlation between EPAS-1 expression and clinicopathological characteristics and its effect on survival. RESULTS: The expression of EPAS-1 protein in renal cell carcinoma and adjacent tissues was 75.9% and 15.9%, respectively. Univariate analysis showed that positive expression of EPAS-1, PT staging, lymphatic metastasis, distant metastasis, and ISUP grade were associated with poor prognosis of renal cell carcinoma (P <0.05); Multivariate analysis results showed that EPAS-1 protein and ISUP classification are independent prognostic factors for renal cell carcinoma. Kaplan-Mier survival analysis showed that the survival rate of renal cell carcinoma patients increased with the expression of EPAS-1 protein decreased significantly (P <0.05). CONCLUSION: The expression of EPAS-1 protein is related to the PT stage, lymphatic metastasis, distant metastasis, and ISUP classification of renal cell carcinoma. EPAS-1 can be used as a potential prognostic marker or Treatment target.