We have previously shown that interferon-γ (IFN-γ) is a potent enhancer of atherogenesis. Interleukin-18 (IL-18) promotes inflammatory responses through release of IFN-γ, although it can also exert direct actions on other inflammatory mediators. In this present study, we determined the effects of IL-18 on atherogenesis and the role of IFN-γ in this response. Male apolipoprotein E^−/− mice (apoe^−/−; aged 16 weeks, n=10/group) were fed a normal diet and injected intraperitoneally for 30 days with either recombinant IL-18 (30 ng/g/day) or saline. Atherosclerotic lesion size was quantified in 2 vascular beds: the ascending aorta and the aortic arch. IL-18 administration did not affect serum cholesterol concentrations or lipoprotein-cholesterol distribution; however, exogenous IL-18 administration increased lesion size 2-fold in both the ascending aorta (50 642±12 515 versus 112 399±13 227 μm², P=0.004; saline versus IL-18 groups, respectively) and the aortic arch (3.1±0.3% versus 6.2±0.9% area, P=0.006). Exogenous IL-18 promoted a 4-fold increase in the number of lesion-associated T lymphocytes (11±3 versus 50±5 cells; P<0.0001) and cells expressing major histocompatability complex class II (9±3 versus 40±6 cells; P=0.0002). To determine the role of IFN-γ production in this response, exogenous IL-18 was administered to apoe^−/− mice that were IFN-γ deficient. These studies demonstrated that lack of endogenous IFN-γ ablated the effects of IL-18 on atherosclerosis. Therefore, these data strongly implicates IL-18 in the atherogenic process and suggests that IL-18 increases lesion development through enhancement of an inflammatory response involving an IFN-γ–dependent mechanism. The full text of this article is available at http://www.circresaha.org.