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In addition to hepatic expression, cholesteryl ester transfer protein (CETP) and hepatic lipase (HL) are expressed by human macrophages. The combined actions of these proteins have profound effects on HDL structure and function. It is not known how these HDL changes influence atherosclerosis. To elucidate the role of leukocyte-derived HL on atherosclerosis in a background of CETP expression, we studied low density lipoprotein receptor-deficient mice expressing human CETP (CETPtgLDLr−/−) with a leukocyte-derived HL deficiency (HL−/− BM). HL−/− bone marrow (BM), CETPtgLDLr−/− mice were generated via bone marrow transplantation. Wild-type bone marrow was transplanted into CETPtgLDLr−/− mice to generate HL+/+ BM, CETPtgLDLr−/− controls. The chimeras were fed a high-fat, high-cholesterol diet for 14 weeks to promote atherosclerosis. In female HL−/− BM, CETPtgLDLr−/− mice plasma HDL-cholesterol concentration during high-fat feeding was decreased 27% when compared with HL+/+ BM, CETPtgLDLr−/− mice (P < 0.05), and this was associated with a 96% increase in en face aortic atherosclerosis (P < 0.05). In male CETPtgLDLr−/− mice, leukocyte-derived HL deficiency was associated with a 16% decrease in plasma HDL-cholesterol concentration and a 25% increase in aortic atherosclerosis. Thus, leukocyte-derived HL in CETPtgLDLr−/− mice has an atheroprotective role that may involve increased HDL levels.