Objective To study the effect and mechanism of neferine (Nef) on macrophage foam cell formation. Methods The mouse RAW264. 7 cells were induced into foam cells by incubation with oxidized low density lipoprotein (ox-LDL) to examine the protective effects of Nef. The cellular lipid accumulation was examined by oil red O staining. The cellular contents of total cholesterol and cholesterol ester were delected by enzymatic colorimetry. The CD36 cell surface protein was determined by immunofluorescence and flow cytometry. The CD36 mRNA was quantified by RT-PCR. Results Compared with ox-LDL group, oil red O-positive cells of Nef protective group were greatly reduced. The cellular contents of total cholesterol and cholesterol ester of Nef protective group were also obviously decreased. Concomitantly, Nef significantly decreased CD36 cell surface protein and mRNA expression induced by ox-LDL. Conclusion Nef could inhibit atherosclerotic foam cell formation through reduction of CD36 expression.