Hematopoietic Stem Cells (HSC) are critical for the success of stem cell transplantation. Autophagy is an intracellular process that has an established role in the long-term survival and function of HSCs. We investigated the contribution of autophagy to HSC in the setting of allogeneic transplantation, in which GVHD results in a T cell derived cytokine storm early post-transplant. Firstly, we demonstrate that TNFa and IL-1b synergistically promote autophagy in both HSC and progenitor populations in vitro. In vivo studies demonstrate that autophagy is increased in donor HSC and progenitor cells in the setting of GVHD compared to non-GVHD controls. Competitive transplant experiments of 1:1 Atg5^-/- fetal liver (FL) with WT FL demonstrated that autophagy deficient cells display reduced capacity to reconstitute. In an MHC mismatch model of GVHD we demonstrated that while Atg5^-/- cells are capable of engraftment they are overcome in the presence of alloreactive T cells and undergo primary graft failure by day 10 post-transplant while WT cells survive and engraft. We confirmed this early graft failure in a second model, using donor VAV^cre x Atg7^fl/fl mice. The essential requirement for autophagy, specifically in early progenitors and HSC, was confirmed using LysM^cre Atg7^fl/fl mice. We demonstrate that autophagy is increased in the GVHD (T cell containing graft) setting and that without autophagy early myeloid precursors fail to provide short term reconstitution leading to primary graft failure and mortality. This primary graft failure can be rescued by the administration of cyclosporine, which works to dampen the T cell induced cytokine storm post-transplant. Thus intervention to increase autophagy in these cells post-transplant may improve engraftment in the clinic.