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The main aim was to examine the association between occupational groups and incident cardiovascular disease (CVD), and to which extent associations are mediated by lifestyle-associated variables (cardiorespiratory fitness, smoking, BMI, exercise, and diet). A total of 304,702 participants (mean age 42.5 yrs., 47% women), who performed a health profile assessment in Sweden between 1982 and 2019, were included in the analyses. CVD incidence was obtained from national registers. All participants were free from CVD prior to the health profile assessment. Occupational group was defined using the Swedish Standard Classification of Occupations and analyzed separately (13 different occupational groups) as well as after aggregation into four occupational groups (white-collar high-skilled, white-collar low-skilled, blue-collar high-skilled and blue-collar low-skilled). Cardiorespiratory fitness, BMI, exercise, smoking, and diet were included as mediators and analyzed separately in single models and simultaneously in one multiple mediation model. All mediation analyses were adjusted for sex, age, length of education and calendar time. White-collar high-skilled was set as reference in all analyses. Blue-collar and low-skilled occupation had a higher risk of incident CVD compared to the reference. Cardiorespiratory fitness, BMI, exercise, smoking, and diet mediated 48% to 54% of the associations between reference and the other aggregated occupational groups. In the single model, the strongest mediators were cardiorespiratory fitness, smoking and BMI. In conclusion, blue-collar and low-skilled occupations had a significantly higher risk for incident CVD compared to white-collar high-skilled workers, with the association mediated to a large extent by variation in lifestyle-associated variables.