In this study, we showed the unique importance of donor-derived myeloid HO-1 in the prevention of lethal experimental GVHD and we corroborated this observation by demonstrating the association between human <i>HMOX1</i> (GT)<sub>n</sub> microsatellite polymorphisms and the incidence of severe acute GVHD in two independent HSCT patient cohorts. This evidence concerns the gene HMOX1 and acute graft versus host disease.