HLA-G is a non-classical class I molecule which induces tolerance in allogeneic situations by inhibition of cytotoxic NK and CD8 + T cells and by induction of regulatory T cells. Concordantly, in solid organ transplantation HLA-G is associated with a lower risk for acute and chronic rejection, whereas its role in allogeneic stem cell transplantation (allo-SCT) is less established. We here present detailed analyses of HLA-G-levels in patients after allo-SCT showing a correlation of elevated soluble HLA-G (sHLA-G) levels with less severe acute (p = 0.06) and chronic GvHD (p = 0.0025) and with a superior overall survival (p = 0.03). Soluble HLA-G levels are also positively correlated with the frequency of regulatory T cells in vivo. These clinical data are corroborated by in vitro analyses showing that patients-derived sHLA-G inhibit allogeneic immune responses. ATG-treatment of patients dominantly affects the sHLA-G levels post allo-SCT. Thus, this study highlights the association of elevated sHLA-G levels with less severe acute and chronic GvHD and provides additional functional analyses elucidating possible tolerance-inducing mechanisms of sHLA-G in the context of allo-SCT.