Author SummaryRheumatoid arthritis (RA) is a systemic autoimmune disorder characterized by chronic inflammation in joint tissues leading to destruction of cartilage and bone. Despite some therapeutic advances, the etiology of RA pathogenesis is not yet clear, and effective treatment of RA remains a significant, unmet medical need. Hypoxia is a prominent feature of inflamed tissue within RA-affected joints, and earlier work has implicated limited involvement of hypoxia-inducible factor (HIF)-1 α. We explored the role of a second HIF family member, HIF-2α, in RA pathogenesis. We showed that HIF-2α is markedly increased in the tissue lining the RA-affected joints. Notably and in contrast to HIF-1α, when overexpressed in normal mouse joint tissues, HIF-2α is sufficient to cause RA-like symptoms. Conversely, an HIF-2α deficiency blocks the development of experimental arthritis in mice. We discovered further that HIF-2α regulates RA pathogenesis by modulating various RA-associated functions of joint-specific fibroblast-like cells, including proliferation, expression of cytokines, chemokines, and matrix-degrading enzymes, and bone-remodeling potential. HIF-2α also increases the ability of these cells to promote interleukin-6–dependent differentiation of TH17 cells, a known effector of RA pathogenesis. We thus show that HIF-1α and HIF-2α have distinct roles and act via different mechanisms in RA pathogenesis.