Objective： To investigate and compare the effect and the possible mechanisms of 2 hypoxia-inducible factors （HIF） 1α and 2α on renal cell carcinoma （RCC） by RNA interference （RNAi） method. Methods： Chemically synthesized HIF- 1α and HIF-2α RNAi were transfected into RCC cell line A498 by liposome transient transfection. Normal proximal tubule cell line HK-2 and A498 were separately treated with medium and liposome as controls. The expressions of VEGF, ET-1, bcl-2 and Ki67 were observed by RT-PCR or Western blot 24 h after RNAi. Cell apoptosis was detected by flow cytometry and fluorescence microscopy. Results： Expressions of HIF-1α and HIF-2α RNAi were higher in A498 than those in HK-2, and the 2 genes were successfully blocked after RNAi. HIF-1α RNAi resulted in a significant decrease of ET-1, bcl-2 and Ki67 expression, with increased apoptosis and necrosis of cells. HIF-2α RNAi only resulted in a decrease of VEGF. Conclusion： Both HIF-1α and HIF-2α play important roles in regulation of angiogenesis; moreover, HIF-1α might also regulate proliferation of tumor cells, possibly through regulating anti-apoptotic genes. It is implied the existance of different transcription regulation functions and gene combining sites between HIF-1α and HIF-2α.