Alleviation of dextran sulfate sodium (DSS)-induced colitis was shown after by transplantation of bone marrow derived cells in mice. Nevertheless, the underlying mechanism remains elusive. In the present study, we transplanted primary mouse mesenchymal stem cells (MSC) into isogeneic mice with DSS-induced colitis. We found that MSC transplantation significantly alleviated the DSS-induced colitis. Inhibition of transforming growth factor beta (TGF-beta) signaling abrogated the therapeutic effect of MSC transplantation on DSS-colitis, suggesting a TGF-beta signaling-dependent manner. Moreover, MSC transplantation seemed to induce M2 macrophage polarization, which appeared to be the major source of TGF-beta in this model. Our data thus demonstrate that MSC transplantation may activate TGF-beta signaling pathways to promote the recovery of DSS-colitis.