This study examined the extent to which the metabolic syndrome (MS) augments the risk for major cardiovascular events in healthy patients with a strong genetic background for coronary artery disease (CAD). In a prospective cohort study, we examined 1,316 patients without previously diagnosed CAD or diabetes mellitus. Patients were participants of the Regensburg Myocardial Infarction Family Study, in which > or = 2 family members had severe CAD and 1 had myocardial infarction (MI) at < 60 years of age. During a 2-year follow-up, the incidence of first cardiovascular events (MI, revascularization, and cardiac death) was compared between those with and without the MS at baseline. In all previously unaffected family members, the presence of MS increased the hazard ratio for first manifestation of CAD by a factor of 1.9 (p = 0.030), which resulted in an event rate of 7.1% during follow-up. Specifically in young patients (< or = 50 years old, n = 422), we identified the MS as a major event predictor that conferred a 5.8-fold increased relative risk for first cardiovascular events compared with patients without the MS (95% confidence interval 1.4 to 23.8, p = 0.015, event rate 6.2%). Remarkably, of the individual MS components, obesity was strongly associated with incident MI (relative risk 4.4, 95% confidence interval 1.5 to 13.0, p = 0.007). Thus, the MS strongly predicts cardiac morbidity and mortality in healthy patients with a family background of CAD.