The clinical relevance of ventricular premature complexes (VPCs) in apparently healthy patients is not clear and is typically not considered when evaluating risk. We conducted a prospective longitudinal study of the population-based Atherosclerosis Risk In Communities (ARIC) study of 15,070 Caucasians and African-Americans, 45 to 64 years of age, to assess the risks of coronary heart disease (CHD) events and mortality associated with VPCs among participants with and without prevalent CHD at baseline. VPCs on a single 2-minute electrocardiogram were identified in 940 participants (6.2%). After a follow-up of >10 years, 1,762 participants died, with 366 deaths related to CHD, and 1,736 had cardiac events. The percentage of participants with CHD mortality was >3 times greater for those with VPCs compared with those without VPCs. After controlling for cardiovascular risk factors and therapy with proportional hazards regression, participants with VPCs were >2 times as likely to die due to CHD than were those without VPCs. Increased risk was found for participants with and without baseline CHD. In conclusion, a clinical finding of VPCs on electrocardiography of even apparently healthy patients may warrant a heightened awareness of and attention to cardiovascular risk assessment and management.