While seroepidemiologic studies first suggested a possible association of prior infection with Chlamydia pneumoniae and atherosclerotic risk, the contribution of seroepidemiologic studies of C. pneumoniae and atherosclerotic risk remains a source of controversy, in part because the reported findings appear inconsistent. In general, cross-sectional studies of C. pneumoniae and atherosclerotic risk suggest an association, but recent reports from several prospective studies failed to demonstrate associations between the presence of IgG antibodies to C. pneumoniae and incident myocardial infarction. Evidence from other paradigms-pathologic, animal experimental, and molecular studies-supports a possible etiologic role for C. pneumoniae in atherothrombotic disease, raising questions about the contribution of seroepidemiologic studies. This review summarizes the major findings from seroepidemiologic studies in the context of other research paradigms, explores alternative explanations for the inconsistent findings, and suggests a further role for seroepidemiologic studies of C. pneumoniae and atherothrombotic risk.