Graft-versus-host disease (GvHD) is a major complication of allogeneic hematopoietic stem cell transplantation (HSCT). Current strategies to prevent GvHD with immunosuppressive drugs carry significant morbidity and may affect the graft-versus-tumor (GVT) effect. We hypothesized that neutralization of BMP signaling using a monoclonal antibody would suppress GvHD and ameliorate immune disorders in vivo. RGMb expression was significantly increased in murine small intestine at 24h post total body irradiation. In an HSCT murine model, 3 doses of anti-RGMb antibody but not the isotype control protected the recipient mice against Tcon-induced GvHD improving survival rate (75% versus 30% at 60 days post-transplantation), while the GVT effect remains intact. Allogeneic Tcon transplantation induced cytokine expressions of IFN-gamma, BMP2, and BMP4 in small intestine tissue. The expression was mitigated by anti-RGMb therapy via induction of anti-inflammatory IL-10 expression. Bioluminescence imaging showed that anti-RGMb treatment reduced Tcon proliferation in vivo, but also, enhanced CD4+ versus CD8+ T cells polarization. The phenotype was further confirmed in vitro where anti-RGMb treatment reduced both naïve CD4+ and naïve CD8+ T cell proliferation in a mixed lymphocyte reaction assay. We also evaluated blocking anti-RGMb antibody therapy in Inflammatory Bowel Disease (IBD). Anti-RGMb antibody in dextran sulfate sodium (DSS) treated-mice prevented body weight loss for a least 8 days, improved survival, and also normalized the colon length unlike with isotype control antibody treated mice. Therefore, blocking anti-RGMb antibody therapy can prevent GvHD following HSCT but also reduce autoimmunity.