Integrin-associated protein (CD47) is a broadly expressed protein that costimulates T cells, facilitates leukocyte migration, and inhibits macrophage scavenger function. To determine the role of CD47 in regulating alloresponses, CD47+/+ or CD47−/− T cells were infused into irradiated or nonconditioned major histocompatibility complex disparate recipients. Graft-versus-host disease lethality was markedly reduced with CD47−/− T cells. Donor CD47−/− T cells failed to engraft in immunodeficient allogeneic recipients. CD47−/− marrow was unable to reconstitute heavily irradiated allogeneic or congenic immune–deficient CD47+/+ recipients. These data suggested that CD47−/− T cells and marrow cells were cleared by the innate immune system. To address this hypothesis, dye-labeled CD47−/− and CD47+/+ lymphocytes or marrow cells were infused in vivo and clearance was followed. Dye-labeled CD47−/− cells were engulfed by splenic dendritic cells and macrophages resulting in the clearance of virtually all CD47−/− lymphohematopoietic cells within 1 day after infusion. Host phagocyte-depleted CD47+/+ recipients partially accepted allogeneic CD47−/− T cells. Thus, dendritic cells and macrophages clear lymphohematopoietic cells that have downregulated CD47 density. CD47 expression may be a critical indicator for determining whether lymphohematopoietic cells will survive or be cleared.