Objective: Atherosclerosis is an inflammatory disease in which T helper 1 (Th1) immunity has been proposed to play an important role. Naı̈ve CD4+ T cells differentiate into interferon-γ (IFN-γ) producing Th1 effector cells when stimulated by interleukin-18 (IL-18) and IL-12. We wanted to directly test whether the Th1 pathway is proatherogenic. Methods: We bred IL-18^−/− mice with apolipoprotein E^−/− (apoE^−/−) mice and assessed atherosclerosis in the aortic root of the offspring. Results: 24-week-old IL-18 deficient apoE^−/− mice exhibited substantially reduced lesion size (93 866±11 273 vs. 144 019±9667 μm² in IL-18^+/+×apoE^−/− mice, P = 0.005). Lesion cells in compound knockout mice displayed reduced I-A^b expression, implying reduced local IFN-γ stimulation. These mice also had an increased proportion of α-SM-actin+ smooth muscle cells, compatible with a more stable lesion phenotype. Immunoglobulin G (IgG) subclass analysis of antibodies to malondialdehyde-modified low density lipoprotein indicated increased Th2 and reduced Th1 helper to B cell antibody production. Surprisingly, serum cholesterol and triglyceride levels were significantly higher in IL-18^−/−×apoE^−/− mice in spite of their reduced atherosclerosis. However, no changes in lipoprotein cholesterol patterns were registered. Conclusion: These data show reduced atherosclerosis and Th1 activity in spite of increased serum cholesterol in IL-18 deficient apoE^−/− mice. They support a proatherogenic role for IL-18.