It is currently thought that acute graft-versus-host disease (GVHD) cannot be elicited in the absence of antigen presentation by radio-sensitive host hematopoietic derived antigen presenting cells (APCs) after allogeneic bone marrow transplantation (BMT). Because clinical data suggest that sex mismatched H-Y antigens may be important minor histocompatibility antigens for GVH responses, we directly tested their relevance and ability to initiate GVHD when presented by either the hematopoietic (host or donor) or the non-hematopoietic derived APCs. H-Y minor antigen incompatibility elicited both CD4(+) and CD8(+) T-cell driven GVHD lethality. Studies with various well-established bone marrow chimera recipients, in contrast to the current views, demonstrated that in the absence of functional radio-sensitive host hematopoietic derived APCs, H-Y antigen presentation by either the donor hematopoietic derived or the host non-hematopoietic derived APCs is sufficient for inducing GVHD. Our data further suggest that infusion of sufficient numbers of alloreactive donor T cells will induce GVHD in the absence of radio-sensitive host hematopoietic derived APCs