AIMS: To examine whether human placenta mesenchymal stem/stromal cells (hpMSCs) mitigate graft-versus-host-disease (GVHD) via regulation of Th17 and Tr1. MATERIALS AND METHODS: hpMSCs or phosphate buffered saline (PBS, as a control) were injected into humanized xeno-GVHD NOD/SCID mouse model. Effects on body weights and survival times were determined. In addition, various assays, including flow cytometry (FCM) and HE stain, were performed on tissues (liver, spleen, lung and intestine) from these hpMSCs versus PBS treated GVHD mice. Th17 cell number in vitro was analyzed by FCM. KEY FINDINGS: hpMSCs reduced weight loss, along with IL-6 and IL-17 production to prolong the survival of GVHD mice. Th17 cell number was down-regulated obviously in hpMSCs treated GVHD mice. Conversely, Tr1 cell number and TGF-β production were enhanced by hpMSCs. Moreover, knockdown of programmed death ligand 2 (PD-L2) increased Th17 cell number from PMA activated T cells co-cultured with hpMSCs. SIGNIFICANCE: hpMSCs can modulate the balance between Th17 and Tr1 cells to alleviate GVHD. In addition, PD-L2 as expressed on hpMSCs inhibits the generation of Th17 subset from activated T cells. These data suggest that hpMSCs attenuate GVHD through inhibition of severe inflammatory responses resulting from T cell differentiation.