Objective— Coronary heart disease is associated with monocytosis. Studies using animal models of monocytosis and atherosclerosis such as ApoE −/− mice have shown bone marrow (BM) hematopoietic stem and multipotential progenitor cell (HSPC) expansion, associated with increased cell surface expression of the common β subunit of the granulocyte macrophage colony–stimulating factor/interleukin-3 receptor (CBS) on HSPCs. ApoE −/− mice also display increased granulocyte macrophage colony–stimulating factor–dependent monocyte production in the spleen. We investigated the role of the CBS in cholesterol-driven HSPC expansion, monocytosis, and atherosclerosis. Approach and Results— Ldlr −/− mice were transplanted with ApoE −/− Cbs −/− or ApoE −/− BM followed by Western-type diet feeding. Compared with ApoE −/− BM–transplanted controls, ApoE −/− Cbs −/− BM–transplanted mice had reduced BM and splenic HSPC proliferation, fewer blood monocytes and neutrophils, and reduced macrophage content and area of early atherosclerotic lesions. More advanced lesions showed diminished macrophage and collagen content; however, lesion size was unchanged, reflecting an increase in necrotic core area, associated with a marked decrease in Abcg1 expression and increased macrophage apoptosis. Compared with wild-type mice, Western-type diet–fed ApoE −/− mice showed increased CBS expression on granulocyte macrophage colony–stimulating factor–producing innate response activator B cells and expansion of this population. ApoE −/− Cbs −/− BM–transplanted Ldlr −/− mice showed a marked decrease in innate response activator B cells compared with ApoE −/− BM–transplanted Ldlr −/− controls. Conclusions— Increased levels of CBS on HSPCs and splenic innate response activator B cells lead to expansion of these populations in ApoE −/− BM–transplanted Ldlr −/− mice, contributing to monocytosis and increased lesional macrophage content. However, in more advanced lesions, the CBS also has a role in atherosclerotic plaque stabilization.