Background and aims Abdominal aortic aneurysm (AAA) is a common disease; however, its exact pathogenesis remains unknown, and no specific medical therapies are available. Interleukin (IL)-18 plays a crucial role in atherosclerotic plaque destabilization and is a strong predictor of cardiovascular death. Here, we investigated the role of IL-18 in AAA pathogenesis using an experimental mouse model. Methods and results After infusion of angiotensin II (Ang II) for 4 weeks and β-aminopropionitrile (BAPN) for 2 weeks, 58% of C57/6J wild-type (WT) mice developed AAA associated with enhanced expression of IL-18; however, disease incidence was significantly lower in IL-18−/− mice than in WT mice (p Conclusions These findings indicate that IL-18 plays an important role in the development of AAA by enhancing OPN expression, macrophage recruitment, and MMP activation. Moreover, IL-18 represents a previously unrecognized therapeutic target for the prevention of AAA formation.