The aim of the present study is to investigate the potential anti-atherogenic effect of 4-hydroxyphenylacetic acid (4-HPAA), a major microbiota-derived metabolite of polyphenols, on macrophagepolarization and the formation of macrophage derived-foam cells as well as the underlying molecular mechanisms. 4-HPAA treatment could-significantly decrease the secretion and mRNA levels of TNF-α, IL-6 and IL-1β of M1 macrophages induced by lipopolysaccharide (LPS) and interferon-γ (IFN-γ),indicating its ability to inhibit the polarization of macrophage cell into pro-inflammatory M1-typemacrophage. The results of oil red O staining revealedthat 4-HPAA significantly inhibited theaccumulation of lipid droplets in a dose-dependent manner compared with the model cells. In addition, 4-HPAA significantly decreased the content of intracellular cholesterol esters.RT-PCR results showed that compared with the model group, 4-HPAA significantly up-regulated ABCG1 and down-regulated CD36 gene expression level (P ＜ 0.05), which was associated with macrophage cholesterol efflux. In conclusion, the results showed that the potential role of 4-HPAA in preventing M1 macrophage polarization and foam cell formation, which may play an important role in the anti-atherogenic effect of polyphenols.