Defects in immune reconstitution after hematopoietic stem cell transplantation confer extreme infection risk on to the transplant recipient. Perturbations in adaptive immune reconstitution have been well characterized, yet defects in reconstituted innate cellular-mediated immunity remain largely unstudied. Recovery in innate effector cells was defined by using an established murine model of autologous bone marrow transplantation. Cytokine induction after cell culture and systemic stimulation with pathogen-associated molecular patterns was also measured for control, transplant-recipient, and irradiated-only animals. Early reconstitution (7 to 14 days) of donor-derived macrophages, dendritic cells, and polymorphonuclear cells was associated with recovery in interleukin (IL)-12p70 and IL-6 production. Later reconstitution (21 days) of natural killer cells was associated with interferon (IFN)-γ recovery. Hence, splenocyte innate cellular-mediated immunity recovered to normal levels in cellularity and IL-12p70, IFN-γ, and IFN-α production by 21 days after transplantation. In contrast, levels of systemic cytokine production from transplant-recipient and irradiated-only animals were preserved despite incomplete or absent hematopoietic reconstitution. These results suggest that innate immune responses to systemic inflammatory challenges are largely intact after autologous bone marrow transplantation, whereas local innate cellular-mediated immunity within reconstituting lymphoid organs may be impaired. The disparate effects of autologous hematopoietic stem cell transplantation on host immune function may translate to differences in susceptibility to local versus systemic infectious challenges.