Retinoic acid (RA), a vitamin A metabolite is produced in the intestine and production increases in response to infection and inflammation. We examined the role of RA in regulating IL-22 production by γδ T cells in intestinal inflammation. RA significantly enhanced IL-22 production by γδ T cells stimulated in vitro with IL-1β or IL-18 and IL-23. In vivo RA attenuated colon inflammation following dextran sodium sulfate (DSS) treatment of mice. This was associated with a significant increase in IL-22 secretion by γδ T cells and enhanced production of the IL-22-responsive antimicrobial peptides Reg3β and Reg3γ in the colon. The attenuating effects of RA on colitis were reversed in TCRδ-defective mice or by treatment with an IL-22 blocking antibody, demonstrating that RA mediates protection by enhancing IL-22 production predominantly from γδ T cells. The molecular events controlling IL-22 transcription are not well defined. Using chromatin immunoprecipitation (ChIP) assays we show that RA promoted binding of RA receptor (RAR) to the IL-22 promoter in γδ T cells. Our findings suggest that RA may shape early intestinal immune responses by promoting IL-22 synthesis by γδ T cells, and provide novel insights into the molecular events controlling IL-22 transcription.