Objective To observe the expression of EPAS-1 in clear cell renal cell carcinoma, analyze its relationship with cell proliferation, investigate clinical significance. Methods 78 patients with clear cell renal cell carcinoma were collected. The tumor tissue was taken as the observation group, and the normal renal tissue(＞3cm from the tumor margin) was taken as the control group. The expression of EPAS-1 of two groups and proliferating cell nuclear antigen (PCNA) of observation group were detected by immunohistochemistry method. Human renal clear cell carcinoma 786-0 cell line and human renal cortex proximal convoluted tubule epithelial HK-2 cell line were selected. The expression of EPAS-1 protein was detected by Western blot, the expression of EPAS-1 mRNA was detected by real-time fluorescence quantitative PCR (qRT-PCR). Human renal clear cell carcinoma 786-0 cell line was selected to establish small interfering RNA EPAS-1(siRNA EPAS-1 group) and a blank control group (NC group). PCNA protein was detected by Western blot and PCNA mRNA was detected by RT-PCR. Results Positive rate of EPAS-1 was significantly higher in clear cell renal cell carcinoma than that in the control group. The positive rate of EPAS-1 was significantly different in Fuhrman grade, diameter and PCNA proliferation index, but was not significantly different in renal sinus involvement, gender and age. The expression of EPAS-1 was related to survival time. The expression of EPAS-1 protein and mRNA was significantly higher in 786-0 cell line than that in HK-2 cell line. The expression of PCNA protein and mRNA was significantly lower in siRNA EPAS-1 group than that in NC group. Conclusion Expression of EPAS-1 is significantly increased in clear cell renal cell carcinoma. Expression of EPAS-1 is different in different clinicopathological features. EPAS-1 may play a role in promoting cell proliferation. The expression of EPAS-1 may be related to the prognosis of tumor.