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.