The use of antimicrobial agents to prevent coronary events is under debate. They have reduced cardiovascular events in some studies, but in others, their effect has not been distinguishable from that of placebo. In addition to Chlamydophila (Chlamydia) pneumoniae as a target pathogen, very few other microbes or infections have been targeted, although an association for instance between cardiovascular disease and periodontitis has been established. In our recent pilot study, long-term clarithromycin treatment reduces recurrent cardiovascular events in subjects without periodontitis, but in subjects with periodontitis, fails to show any effect. As a background infection, periodontitis may overpower the beneficial effects of antibiotics. This paper presents the hypothesis that periodontitis is behind the failure of antibiotics to prevent coronary events. We discuss the systemic effects of periodontal infection and consider studies to test our hypothesis, which offers a novel viewpoint for discussion of antibiotics in coronary-disease prevention.