Objective-Using bone marrow transplantation, we assessed the impact of macrophage-derived phospholipid transfer protein (PLTP) on lesion development in hypercholesterolemic mice that expressed either normal levels of mouse apolipoprotein AI (apoAI) or elevated levels of only human apoAI. Methods and Results-Bone marrow transplantations were performed in low-density lipoprotein receptor-deficient mice (LDLrϪ/Ϫ) that expressed either normal levels of mouse apoAI (msapoAI) or high levels of only human apoAI (msapoAIϪ/Ϫ, LDLrϪ/Ϫ, huapoAITg). Mice were lethally irradiated, reconstituted with either PLTP-expressing or PLTP-deficient bone marrow cells, and fed a high-fat diet over 16 weeks. Macrophage PLTP deficiency increased atherosclerosis in LDLrϪ/Ϫ mice with minimal changes in total plasma cholesterol levels. In contrast, the extent of atherosclerosis in msapoAIϪ/Ϫ, LDLrϪ/Ϫ, huapoAITg mice was not significantly different between groups that had received PLTPϪ/Ϫ or PLTPϩ/ϩ bone marrow. In vitro studies indicated that PLTP deficiency led to a significant decrease in ␣-tocopherol content and increased oxidative stress in bone marrow cells. Conclusions-Our observations suggest an atheroprotective role of macrophage-derived PLTP in mice with normal apoAI plasma levels. The atheroprotective properties of macrophage-derived PLTP were not observable in the presence of elevated plasma concentrations of apoAI.