Epidemiologic research has shown a correlation between cigarette smoke and the risk of developing atherosclerosis and associated pathological processes including abdominal aortic aneurysms (AAA). Hyperlipidemia and hypertension are additional risk factors for atherosclerosis. The hyperlipideamic apolipoprotein e-knockout (ApoE-/-) mouse is a well-established animal model system for studying the mechanisms of the atherosclerotic process. In this study, we examined the mechanistic effects occurring as three risk factors interact in the atherosclerotic process. Hypertension was induced in hyperlipidemic apolipoprotein-e-knockout (ApoE-/-) mice by application of angiotensin-II and the mice were exposed to mainstream smoke from the reference cigarette 2R4F (University of Kentucky) for 30 days. AAA formation was seen only in angiotensin-ii treated ApoE-/--mice. The incidence and severity of AAA were further increased by smoke exposure. Expression of matrix metalloproteinases-(MMP)-2, -3, -8, -9, and -12 in AAA was enhanced in smoke-exposed angiotensin-II treated hyperlipemic mice. Zymographic activity analysis revealed that the activity of MMP-9 and MMP-2 was highest in the mice exposed to all three risk factors. This study showed for the first time that formation and severity of AAA in hypertensive and hyperlipidemic ApoE-/- mice are accelerated by exposure to cigarette mainstream smoke, suggesting that this animal model may be suitable for studying mechanisms of AAA development.