Crif1 is a mitochondrial protein that acts as a translational factor for mitochondrial DNA and its knockdown results in impaired mitochondria oxidative phosphorylation (OXPHOS) and promotes ROS production. On the other hand it is associated with transcriptional activity of STAT3 via direct interaction. In this study, we examined whether Crif1 has an immunoregulatory potential via modulating the differentiation and function of pathogenic T cells. To verify this hypothesis, the actions of Crif1 in rheumatoid arthritis (RA), systemic autoimmune disease characterized by a hyperplasia of synovial tissue and progressive destruction of articular cartilage structure impinged by pathogenic immune cells such as Th17 cells, was investigated. We found that deficiency of Crif1 in CD4+ cells promoted the production of IL-17. Crif1 overexpression in collagen-induced arthritis (CIA) mice attenuated the clinical and histological severities of inflammatory arthritis. Furthermore, overexpression of Crif1 in arthritis mice significantly reduced osteoclast differentiation from bone marrow cells. These data suggest that the potential role of Crif1 in modulating of Th17 cells and osteoclasts in RA.