Graft-versus-host disease (GvHD) and graft rejection have remained significant complications of allogeneic stem cell transplantation. Mesenchymal stem cells (MSCs) from the bone marrow have been shown to suppress T-cell activation in vitro and in vivo, and may be used to reduce GvHD in the recipient or to facilitate engraftment across MHC barriers. MSCs can be derived from a variety of tissues. Thus, we asked whether MSCs from different tissues might have differential effects on T-cell responses. We were particularly interested in MSCs derived from adipose tissue because of its abundance and accessibility. We investigated and compared the immunosuppressive potential of murine MSCs derived from muscle tissue, adipose tissue, omentum, and bone. Cells from the different tissues were enriched for MSCs and cultured for 2-3 weeks to deplete hematopoietic cells. Mixed lymphocyte reactions (MLRs) including MSCs were performed using concanavalin A or allogeneic T cells as inducers of T-cell activation. MSCs from all tissues differentiated into multiple lineages. Mitogen-induced T-cell activation, as well as allogeneic T-cell responses, was reduced in MLRs mediated by the addition of MSCs. Reduction of T-cell activation was most pronounced for muscle tissue in the mitogen-induced MLR and fat tissue during the allogeneic MLR. These data demonstrate that MSCs from multiple tissues efficiently reduce T-cell activation. The results suggest that MSCs from adipose tissue can serve as an alternative source for MSCs to bone or bone marrow for the modulation of GvHD after allogeneic stem cell transplantation or to enhance engraftment across MHC barriers.