Apolipoprotein E (ApoE) plays an important role in the development of atherosclerosis. Previous studies provide evidence for an atheroprotective role of ApoE in mouse models on the ApoE deficient (ApoE-/-) background. However, it is not clear whether this is also true on the LDL-receptor deficient (LDLR-/-) background. Transgenic mice carrying hApoE coding sequences in a chicken lysozyme expression cassette were generated. Transgene expression was directed into macrophages, expressing low levels of hApoE. Expression of the hApoE transgene was not sufficient to correct hypercholesterolemia. However, lesion area at the brachiocephalic artery (BCA) was significantly reduced (-72%) in female hApoE transgenic mice on the LDLR-/- background. This was associated with increased cholesterol efflux in macrophages of transgenic animals on the ApoE-/- background. We conclude that over-expression of ApoE in macrophages might be useful as a therapeutic principle for the prevention of atherosclerosis.