Objective— The aim of this study was to investigate the influence of interferon-γ (IFN-γ) on atherosclerosis in low density lipoprotein receptor (LDLR)–null mice. Methods and Results— We cross-bred IFN-γ–deficient mice with LDLR-null mice and analyzed lipoprotein profiles and atherosclerosis in the compound mutant progeny after 8 and 20 weeks on a cholesterol-enriched diet. IFN-γ deficiency did not affect serum cholesterol levels or lipoprotein profiles, but it did affect the extent and phenotype of atherosclerosis. Atherosclerotic lesions in IFN-γ–deficient mice were reduced by 75% in the aortic arch and by 46% in the descending aorta compared with control mice after 8 weeks on the diet. After 20 weeks, arch lesions were reduced by 43%, and descending aorta lesions were reduced by 65% in IFN-γ–deficient mice compared with controls. At 8 weeks, percent lesional macrophage and smooth muscle content was significantly less in the IFN-γ–deficient mice, but not at 20 weeks. Although there were fewer class II major histocompatibility complex–positive cells in the lesions of IFN-γ–deficient animals compared with controls, class II major histocompatibility complex expression on endothelial cells overlying lesions persisted in the absence of IFN-γ. Conclusions— These data provide direct evidence that IFN-γ influences atherosclerosis development and phenotype in the LDLR-deficient mouse, independent of changes in blood lipoprotein profiles.