Background - Expression of the VLDL receptor, primarily in macrophages, has been confirmed in human and rabbit atherosclerotic lesions. The high binding affinity of the VLDL receptor for remnant particles implicates the VLDL receptor pathway in the foam cell formation mechanism in macrophages. This study investigates the effect of interferon (IFN)-γ on VLDL receptor expression in phorbol-12-myristate-13-acetate (PMA)-treated THP-1, HL-60 macrophages, and human monocyte-derived macrophages. Methods and Results - THP-1 cells were induced to differentiate into macrophages by PMA treatment. IFN-γ was added to the medium, and expression of the VLDL receptor was determined. 125I-β-VLDL degradation study and oil red O staining were examined. In THP-macrophages, VLDL receptor protein expression decreased at 2 days after PMA treatment but increased at 3 days and increased up to 5 days. Scavenger receptor proteins, which were not originally present, appeared at 3 days after PMA treatment. IFN-γ inhibited VLDL receptor expression in a dose-and time-dependent manner in macrophages. However, no inhibitory effect was observed in monocytes. Moreover, IFN-γ receptor mRNA increased during differentiation to macrophages. 125I-β-VLDL degradation study and oil red O staining showed that IFN-γ significantly inhibited foam cell formation after the uptake of β-VLDL. LDL receptor-related protein (LRP) and LDL receptor mRNAs were not expressed in macrophages. In PMA-treated HL-60 macrophages and human monocyte-derived macrophages. IFN-γ also inhibited VLDL receptor expression and foam cell formation by β-VLDL. Conclusions - VLDL receptor expression is upregulated during monocyte-macrophage differentiation. IFN-γ inhibits VLDL receptor expression and foam cell formation only in macrophages. Remnant particles induce macrophage foam cell formation through the VLDL receptor pathway.