Pathologic findings and cross-sectional epidemiologic studies suggest that past infection with Chlamydia pneumoniae is associated with clinical and subclinical atherosclerotic disease, although evidence from prospective studies is still scarce. The association between chronic infection by C. pneumoniae and incident coronary heart disease (CHD) was investigated in a case-cohort study conducted among participants in the Atherosclerosis Risk in Communities Study who were free of CHD at the baseline examination (1986–1989). Levels of C. pneumoniae immunoglobulin G (IgG) antibodies in serum collected at baseline from 246 incident cases of CHD identified during follow-up (median, 3.3 years; maximum, 5 years) were compared with those from a stratified sample of the baseline cohort (n = 550). Among incident CHD cases, 65% had IgG antibody titers >1:64, compared with 55% of noncases (compared with negative IgG titers, the relative hazard of CHD was 1.6 (p < 0.01)). In multivariate analyses controlling for other risk factors (age, gender, smoking, serum cholesterol, hypertension, diabetes mellitus, and educational level), the above estimates were substantially reduced and became statistically nonsignificant (relative hazard = 1.2). A significantly increased CHD hazard associated with IgG antibody titers >1:64 was observed among nonsmokers, even after adjustment for other risk factors. Overall, these results do not provide strong support for the hypothesis that C. pneumoniae infection is a risk factor for clinical CHD. Studies with longer follow-up periods will be necessary to determine whether C. pneumoniae infection is involved as an etiologic factor in earlier phases of atherogenesis. Am J Epidemiol 1999;150:149–56.