The tumor suppressor protein p53 is an essential molecule in cell proliferation and programmed cell death (apoptosis), and has been postulated to play a principal part in the development of atherosclerosis. We have examined the effect of p53 inactivation on atherogenesis in apoE-knockout mice, an animal model for atherosclerosis 1, 2. We found that, compared with p53+/+/apoE–/–mice, p53–/–/apoE–/–mice developed considerably accelerated aortic atherosclerosis in the presence of a similar serum cholesterol in response to a high-fat diet. Furthermore, the atherosclerotic lesions in p53–/–/apoE–/–mice had a significant (~ 280%) increase in cell proliferation rate and an insignificant (~ 180%) increase in apoptosis compared with those in p53+/+/apoE–/–mice. Our observations indicate that the role of p53 in atherosclerotic lesion development might be associated with its function in cell replication control, and that p53-independent mechanisms can mediate the apoptotic response in atherosclerosis.