Background Epidemiological studies have reported a link between serum LBP (lipopolysaccharide-binding protein) levels and lifestyle-related diseases. However, there have been no longitudinal studies investigating the association of serum LBP levels and the incidence of cardiovascular disease (CVD) in general populations. Methods and Results A total of 2568 community-dwelling Japanese individuals 40 years and older without prior CVD were followed for 10 years (2002-2012). Serum LBP levels were divided into quartiles (quartile 1: 2.20-9.68 μg/mL; quartile 2: 9.69-10.93 μg/mL; quartile 3: 10.94-12.40 μg/mL; quartile 4: 12.41-24.34 μg/mL). The hazard ratios (HRs) and their 95% CIs for the incidence of CVD were computed using a Cox proportional hazards model. During the follow-up period, 180 individuals developed CVD. The age- and sex-adjusted cumulative incidence of CVD increased significantly with higher serum LBP levels (P for trend=0.005). Individuals with higher serum LBP levels had a significantly greater risk of the development of CVD after adjusting for conventional cardiovascular risk factors (quartile 1: HR, 1.00 [reference]; quartile 2: HR, 1.04 [95% CI, 0.60-1.78]; quartile 3: HR, 1.52 [95% CI, 0.92-2.51]; and quartile 4: HR, 1.90 [95% CI, 1.17-3.09]; P for trend=0.01). This association remained significant after additional adjustment for homeostasis model assessment of insulin resistance (P for trend=0.01). However, when additional adjustment was made for high-sensitivity C-reactive protein, the association was attenuated to the nonsignificant level (P for trend=0.08). Conclusions The present findings suggest that higher serum LBP levels are associated with increased risk of the development of CVD in the general Japanese population. Low-grade endotoxemia may contribute to the pathogenesis of CVD through chronic systemic inflammation.