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Cardiovascular and cerebrovascular diseases (CVD) were found to be associated with overwork in Asia countries, as was death from overwork or known as karoshi. Emerging evidences pointed out a strong dose-response association between working long hours and risk of CVD. However, there was little information concerning the effect of metabolic syndrome on CVD mortality in patients with overwork or without overwork. The aim of this study was to investigate the risk of karoshi from overwork among bus drivers with metabolic syndrome (MetS).In the Taiwan Bus Driver Cohort Study during the period 2005–2012, 1014 professional drivers completed comprehensive studies. Working pattern questionnaire, job stress questionnaires, Swedish occupational fatigue inventory, stress satisfaction offset score (SSOS), biochemical measurements, and physical examinations were used to assess the overwork status and the presence of metabolic syndrome. This cohort was linked to the National Health Insurance Research Dataset to determine whether these workers had higher risk of karoshi from overwork.There were 1014 enrolled bus driver with mean age of 41.05±7.83. The demographic characteristics, biochemical indices, and job stress scores of drivers were presented. For cardiovascular disease mortality, the unadjusted HRs for participants with MetS were 2.00 (95% CI: 1.47 to 2.73; p<0.001) with comparison to those without MetS. After additional adjustment of pertinent variables, positive association remained essentially unchanged (HR=1.47, 95% CI: 1.04 to 2.09; p=0.030). In terms of individual metabolic risk components for cardiovascular disease mortality, BMI, high blood pressure, and high fasting glucose were found to be statistically significant for risk of mortality. After adjusting for covariates, BMI and high blood pressure were two important predictors of CVD mortality.Our study highlighted that the incurrence of metabolic syndrome in bus driver combined with overwork was associated with increased cardiovascular mortality. Regarding metabolic components, BMI and high blood pressure were prognostic predictors of CVD mortality.