Macrophage cholesterol accumulation and foam cell formation are the hallmarks of early atherogenesis. Many plant polyphenols have been shown to inhibit macrophage foam cell formation and the development of atherosclerotic lesions. However, the effect of pomegranate peel polyphenols on foam cells remains unclear. In this study, the potential atheroprotective actions of pomegranate peel polyphenols on cholesterol accumulation and outflow in raw264.7 macrophages, and the mechanisms, were investigated. The results showed that the pomegranate peel polyphenols reduced ox-LDL internalization to diminish foam cell formation, as measured by oil-red O staining in raw264.7 macrophages, which may be due to decreasing the macrophage CD36 protein expression and not SR-A. In addition, pomegranate peel polyphenols promoted apoA-1-mediated macrophage cholesterol efflux by up-regulating ABCA1 and LXRα at the mRNA and protein levels, independently of ABCG1 and PPARγ.