Abstract Body: Atherosclerosis exhibits pronounced sex differences, yet the immunological mechanisms underlying these disparities remain incompletely defined. Using adoptive transfer of apoB100-specific CD4+ T cells into human APOB100–transgenic Ldlr-/- mice, we demonstrate that males develop significantly smaller atherosclerotic lesions and lower plasma cholesterol and triglyceride levels than females, with marked reductions in VLDL. This protection is mediated by androgen-dependent polarization of apoB100-specific CD4+ T cells toward a Th1 phenotype with increased interferon-γ (IFN-γ) production, leading to suppression of hepatic SREBF1, a central regulator of VLDL synthesis. Integrative analyses of murine liver metabolomics, transcriptomic data from human livers of patients with cardiovascular disease, and single-cell RNA sequencing of human atherosclerotic plaques reveal a male-specific inverse association between IFNG and SREBF1 expression. Consistent with these observations, IFN-γ directly inhibits SREBF1 expression in human hepatocytes in vitro. These findings identify a sex-specific immune–hepatic axis in which IFN-γ mediated regulation of lipid metabolism limits VLDL production and attenuates atherosclerosis in males, providing a mechanistic framework for sex-informed therapeutic strategies in atherosclerotic cardiovascular disease.