Aim To investigate the effect of over-expression of Atg5 protein on the degree of macrophage foam.Methods Raw264.7 macrophages were infected with Atg5 lentivirus and control virus. The control cell line (control group) and the Atg5 over-expression cell line (observation group) were established. Two groups of cells were added 50 mL/L ox-LDL (oxidized low-density lipoprotein) respectively to induce the formation of frothy cells. The levels of protein p62, LC3, CD36 and SR-A were analyzed by western blot. The changes of intracellular cholesterol metabolism (cholesterol CE, free cholesterol FC and total cholesterol TC) were detected by HPLC (high performance liquid chromatography).The contents of lipid droplets in the two groups were analyzed by immunofluorescence and electron microscopy. The levels of inflammatory factors including TNF-α, IL-6 and IL-1 beta were detected by ELISA in cell culture supernatants of two groups. Results Compared with the control group, the level of the autophagic substrate p62 was significantly down-regulated and the level of LC3-II was significantly up-regulated in the observation group (P<0.05). Compared with the control group, the contents of CE, FC and TC of macrophages in the observation group significantly decreased (P<0.05).The level of cell lipid and the number of lipid droplets in the observation group were significantly lower than those in the control group (P<0.05). Compared with the control group, the levels of inflammatory cytokines TNF-α, IL-6 and IL-1 beta in the observation group were significantly down-regulated (P<0.05).Conclusions The over-expression of Atg5, autophagy core protein, can significantly enhance the autophagy level of macrophages. The Atg5 may degrade intracellular cholesterol and other lipids to prevent macrophage froth, thus reducing the occurrence of atherosclerosis.