TNF receptor (TNFR)–associated factor TRAF6 is a key activator of NF-κB, playing a critical role in the regulation of innate immune responses and their connection to adaptive immune responses. TRAF6 interactions determine receptor-induced cell death versus survival. TRAF6 has been implicated in cancer but its contributions have not been investigated deeply. In this study, we show that TRAF6 upregulates expression of hypoxia-inducible factor (HIF)–1α. TRAF6 affects HIF-1α protein levels but has little effect on mRNA level. TRAF6 increases HIF-1α protein independent of oxygen. We found that TRAF6 binds HIF-1α and mediates its K63-linked polyubiquitination. The E3 ligase activity of TRAF6 was required to increase HIF-1α protein levels. Finally, we showed that TRAF6 promoted tumor angiogenesis and growth. Our results reveal how TRAF6 functions to upregulate HIF-1α expression and promote tumor angiogenesis. Cancer Res; 73(15); 4950–9. ©2013 AACR.