We have shown recently that administration of exogenous interferon-γ (IFN-γ) to apolipoprotein E (apoE)^-/- mice augmented atherogenesis. In the present study, we examined whether deficiency of endogenous IFN-γ would reduce atherosclerosis in apoE^-/- mice. Compound-deficient mice were generated by crossing strain-matched IFN-γ^-/- and apoE^-/- mice and comparing them to apoE^-/- mice. Groups of both genders were fed either a normal or a high-fat diet. IFN-γ deficiency did not affect serum cholesterol concentrations or lipoprotein-cholesterol distributions in any groups. IFN-γ deficiency had no effect on serum triglyceride concentrations, except for an increase noted in males fed a normal diet. The extent of atherosclerosis was determined in tissue sections of the ascending aorta and on the surface of the aortic arch. During feeding of normal diets, IFN-γ deficiency had no effect on the extent of atherosclerosis in female mice in either vascular bed. In contrast, in male mice fed normal diet, IFN-γ deficiency markedly decreased lesion size in both vascular beds. During feeding of high-fat diets, IFN-γ deficiency also had no effect on lesion size in females but profoundly decreased lesion size in the aortic root of male mice. IFN-γ deficiency had no effect on the abundance of T lymphocytes or MHC class II-positive cells in aortic root lesions of females. By comparison, both these parameters were reduced in lesions of male mice. Therefore, IFN-γ deficiency decreased atherogenesis, potentially by decreasing T lymphocyte presence and cell activation, without influencing serum cholesterol concentrations. However, this effect is strikingly restricted to male mice.