Neutrophil numbers must be tightly controlled to maintain host protection and prevent neutrophil-mediated tissue injury. CD18 deficiency leads to neutrophilia and myeloid hyperplasia in the bone marrow (BM). These studies examined the function of CD18 in regulating neutrophil production and determined whether the defects in neutrophil production that are observed in CD18 deficiency persist in the presence of wild-type (WT) leukocytes that confer host protection. Neutrophil production was evaluated in CD18(-/-) mice and lethally irradiated WT mice reconstituted with mixtures of CD18(-/-) and WT stem cells. Neutrophil kinetic studies suggest that CD18 may facilitate the release of the most mature neutrophils into the circulation. The proportion of CD18(-/-) neutrophils in chimeric animals was greater than the proportion of CD18(-/-) donor cells used to reconstitute the mice, and the percentage of CD18(-/-) leukocytes that were neutrophils was greater than for WT leukocytes, indicating that CD18 may regulate the lineage distribution of hematopoietic cells in the blood and BM. The proportion of Annexin V+ Gr-1+ cells in both the BM of chimeric animals and in vitro cultures of WT and CD18(-/-) hematopoietic stem cells was lower in CD18(-/-) than in WT cells, suggesting that CD18 modulates apoptosis. These data suggest that CD18 directly regulates neutrophil production, in part by limiting the survival of neutrophils and their precursors. Thus, the granulocytosis observed in CD18(-/-) mice and CD18-deficient patients is due to both defects in host defense and BM-intrinsic functions of CD18 in regulating neutrophil production.