Whether working conditions contribute to social inequalities in cardiovascular disease is still a matter of debate. The present study investigates the extent to which the social gradient in the incidence of common behavioral and clinical risk factors is explained by work environment. In a well-characterized cohort of 20,625 middle-aged French civil servants followed for 25 years, social status and work environment were globally measured at baseline by combining respectively four socioeconomic indicators (education, wealth, income, occupational grade) and 25 physical, biomechanical, organizational and psychosocial occupational exposures. These 2 global measures are strongly correlated with each other (p < 0.0001), lower is social status, worse is work environment. In proportional hazard regression models adjusted for sex, age and parental cardiovascular disease, low social status increases the incidence of 9 risk factors with hazard ratios ranging from 1.12 to 1.72 while bad work environment increases the incidence of 7 risk factors with hazard ratios ranging from 1.15 to 2.02. Structural equation models to discrete-time survival analysis with moderated mediation show that bad work environment explains nearly 50% of the global effect of low social status on the incidence of the 9 risk factors (p < 0.01). This mediating effect varies substantially from one risk factor to another, explaining 32–39% of social gradients in the risk of physical inactivity, obesity, diabetes, dyslipidemia and 64–90% of gradients in the risk of hypertension, sleep complaints and depression (all p < 0.01). No significant mediating effect of work environment is found for social gradients in the incidence of non-moderate alcohol consumption and smoking. These results suggest that work environment mediates a large part of the social gradient in the incidence of several common cardiovascular risk factors, emphasizing the necessity to include working conditions in policies aimed to reduce social inequalities in health.