There was little information concerning the combined effect of occupational psychosocial hazards such as long working hours, high job stress, and high fatigue on the risk of cardiovascular and cerebrovascular diseases (CVD). The aim of this study was to investigate the interaction among occupational psychosocial hazards and the impact of metabolic syndrome (MetS) on the risk of CVD among bus drivers. The Taiwan Bus Driver Cohort Study involving 1014 professional drivers was established in 2005 and comprehensively studied. The interactions among occupational psychosocial hazards and the impact of MetS on the risk of CVD were measured. A working pattern questionnaire, job stress questionnaires, the Swedish occupational fatigue inventory, the stress satisfaction offset score, biochemical measurements, and physical examinations were used to assess psychosocial hazards and the presence of metabolic syndrome. There were 707 eligible bus drivers with a mean age of 43.5years old. During the 8-years of follow-up, 77 drivers were diagnosed with CVD. Long working hours, high job stress, and high fatigue were associated with an increased risk of cardiovascular disease incidence in the multivariate analysis. There were synergistic effects among long working hours, high job stress, and high fatigue only in drivers with MetS. A combination of long working hours, high job stress, and high fatigue increased the risk of developing CVD in bus drivers with MetS.