The tumor-promoting factors β-catenin and hypoxia-inducible factor (HIF) are often found to be coactivated in rapidly growing tumors. Recently, it was shown that HIF-1α negatively regulates Wnt/β-catenin signaling by sequestering β-catenin from β-catenin/T-cell factor (TCF). However, no investigation has been undertaken on the involvement of HIF-2α in β-catenin regulation. In this study, it was found that, like HIF-1α, HIF-2α interacts with β-catenin, but at a different site. Furthermore, HIF-2α was found to assemble with β-catenin/TCF and facilitate gene transcription. Mutational analyses revealed that transactivation domains of HIF-2α promote p300 coactivator recruitment by β-catenin. Furthermore, HIF-2α and β-catenin were found to associate in the nuclei of 786-0 renal cell carcinoma cells, and HIF-2α was found to be required for β-catenin activation in these cells and for their proliferation. These results suggest that this interaction contributes to the unrestrained growth of tumor cells containing coactivated HIF-2α and β-catenin. Interestingly, these actions of HIF-2α oppose those of HIF-1α on β-catenin and cell growth, and this suggests that HIF-1α/HIF-2α balance may importantly determine cell growth when hypoxia and Wnt stimulation coexist.