Infection with a human herpes virus, particularly cytomegalovirus (CMV), has been hypothesized to be a cofactor in the development of atherosclerosis in humans. We investigated the association of prior CMV infection with the presence of atherosclerosis in the coronary arteries of the native heart of 314 individuals undergoing heart transplantation. Age, male gender, race, tobacco use, and previous general and cardiac surgery were also studied as covariables. Factors associated with the presence of coronary atherosclerosis by univariate analysis were age greater than the median of 48 years (odds ratio [OR] = 5.9, 95% confidence intervals [CI] 3.0-11.6; P < 0.0001), tobacco use (OR = 3.8, 95% CI 2.1-7.0; P < 0.005), CMV seropositivity (OR = 3.1, 95% CI 1.8-5.5; P < 0.001), and male gender (OR = 3.0, 95% CI 1.6-5.4; P < 0.0005). When patients were divided into quartiles based on age, coronary atherosclerosis was shown to be associated with CMV seropositive status only in the youngest quartile of patients (OR = 3.6, 95% CI 1.4-8.9; P < 0.01) but not in the older three quartiles of patients (OR = 0.9, 95% CI = 0.3-2.4; P > 0.5). In multiple logistic regression analyses, CMV seropositivity was not a significant independent variable in the whole group of patients (P = 0.13) but remained a significant variable in the youngest quartile of patients (P = 0.01). However, 43% of these younger patients and 29% of all patients with coronary atherosclerosis were seronegative for CMV.(ABSTRACT TRUNCATED AT 250 WORDS)