We tested the hypothesis that higher levels of bilirubin, a bile pigment with antioxidant properties, are associated with a decreased risk of cardiovascular disease (CVD). This study analyzed data from the Korean Health and Genome Study to examine the association between serum total bilirubin (TB) on CVD and CVD death. Serum TB was measured in a total of 8,844 subjects (4,196 males and 4,648 females) and evaluated for the development of new onset CVD from 2001 to 2012 (mean 8.1 years of follow-up). During the follow-up period, 689 cases of incident CVD (7.8%) were identified, and the prevalence of metabolic syndrome (MetS) at baseline was 26.1%. The prevalence of MetS decreased across bilirubin tertile categories. In addition to MetS itself, individual components of MetS significantly decreased with increased bilirubin tertiles. Moreover, the incidence of CVD decreased across bilirubin tertile categories. The hazard ratios (HRs) for developing coronary heart disease (CHD, HR 0.769, 95% CI 0.655-1.000) and CVD death (HR 0.513, 95% CI 0.267-0.985) was significantly lower in the highest tertile group (> 0.63 mg/dL) in comparison to the lowest tertile group (< 0.44 mg/dL) after adjusting for all confounding variables. In the present longitudinal study, a significant negative relationship was demonstrated between baseline bilirubin levels and incident CHD and CVD death.