Coronary angioplasty causes vessel wall injury and induces a smooth muscle cell (SMC) proliferative response similar to the healing response of other tissues. This response is so excessive in 25 to 50% of patients that it leads to coronary recurrent stenosis (restenosis). On the basis of an earlier proposal that atherosclerosis (also characterized by SMC proliferation) might be a form of benign neoplasia, we hypothesized that the restenosis process may be driven by alterations that confer to cells a selective growth advantage; upon activation, as by injury, such cells would undergo excessive proliferation. We investigated two potential mechanisms: (i) dysfunction of p53, a tumor suppressor protein that inhibits cell cycle progression and that is functionally inactivated in many human cancers, and (ii) activation of latent HCMV, a herpesvirus associated with atherosclerosis development. Conceivably, an interaction between an HCMV protein(s) and p53 could impair the latter's growth suppressor function, as is the case for proteins encoded by several DNA tumor viruses, including adenovirus, human papillomavirus, simian virus 40, and Epstein-Barr virus. We studied patients who developed restenosis following angioplasty. Because coronary atherectomy (removal of the stenotic tissue by angioplasty) was performed to reopen the renarrowed vessel, we were able to study the tissue of the restenotic lesion. Of 60 lesions examined, nearly 40% had evidence of altered p53 function, which correlated with the presence of HCMV in the lesions. We also found that HCMV and one of the proteins it produces interacts with p53 in a way that suggests it may interfere with its normal inhibitory function. Thus, HCMV mediated inhibition of p53 function may contribute to the development of restenosis. Because restenosis shares many features with atherogenesis, HCMV-mediated inhibition of p53's growth suppressor function may also be important in atherogenesis.