Abstract Background The contribution of psychosocial stress in the workplace to development of type 2 diabetes mellitus (T2DM) is not well investigated. As most studies were conducted in Europe, a further test from the USA seems well justified. The objective of the current investigation was to examine prospective associations of work stress based on the effort-reward imbalance model with risk of T2DM in a national sample of US workers. Method Using data from the national population-based Mid-life in the United States (MIDUS) study with a prospective cohort design and a 9-year follow-up period, the effects of a ratio combining data on effort and reward at work (ER ratio) at baseline on risk of T2DM at follow-up were examined in 1493 workers who were free from diabetes at the baseline survey, applying multivariable Poisson regression analysis. Results During the follow-up, 109 individuals (7.30%) reported onset of diabetes. The analyses demonstrated a significant association between continuous data of the E-R ratio and risk of diabetes (RR and 95% CI = 1.22 [1.02, 1.46]), after adjustment for modifiable and non-modifiable risk factors at baseline. A dose-dependent response was observed with trend analysis when using quartiles of the E-R ratio. Conclusion In the US workers, high effort in combination with low reward at work was significantly associated with elevated risk of T2DM 9 years later. The risk profiles of diabetes should be adapted in consideration of psychosocial work environment and taken into account by conceptualizing prevention programs of chronic non-communicable diseases.