Law enforcement officers (LEO) experience higher levels of work-related stress as compared to the general population, and it has been suggested that these increased stress levels may contribute to increased cardiovascular disease (CVD) risk. The purpose of this study was to determine the relationship between work-related stress and CVD by examining inflammatory mediators in a cohort of LEO. Eighty LEO were segregated into high and low perceived stress categories and matched based on age, ten-year Framingham cardiovascular disease risk, and metabolic syndrome. Circulating levels of inflammatory mediators (C-reactive protein, interleukin-l[Beta], interleukin-6, and tumor necrosis factor-[Alpha]) and work-related stressors (effort/reward imbalance, job strain, social support, vital exhaustion) were assessed and compared between the 40 pairs. Work-related stressors (vital exhaustion and, less so, effort/reward imbalance) explained 63.5% of the elevated perceived stress in the high stress LEO group. IL-6 tended to be higher (p = 0.043) and IL-l[Beta] tended to be lower (p =0.061) in high stressed officers. In contrast, a matrix correlation revealed no significant patterned relationship between perceived stress, the work-related stressors and the inflammatory mediators associated with CVD. These results suggest that despite modest differences in inflammatory mediators between high- and low- stressed officers, neither stress nor work-related forms of stress contribute to CVD via an association with inflammatory mediators.