Hypothesis Previous work suggested no or inconsistent associations between components of work-related stress and type 2 diabetes risk, but suggested sex-specific differences should be further investigated, as women potentially had higher risks. Methods We analyzed data from 73 517 women, mostly teachers, from the E3N cohort study followed for 22 years (1992-2014), to study the association between mentally tiring work, used as a proxy of job demands, and type 2 diabetes risk. Univariate and multivariable Cox regression models were used to estimate hazard ratios and 95% confidence intervals. Results A total of 4187 incident cases of type 2 diabetes cases were observed. There was a higher type 2 diabetes risk for women with a 'Very mentally tiring work' when compared to women with 'Little or not mentally tiring work' (HR = 1.21 (1.09-1.35)). This association was independent of unhealthy lifestyle and traditional metabolic factors. An interaction between mentally tiring work and BMI was detected (P < 0.0001), with a stronger association being observed in non-overweight women, HR = 1.26 (1.08-1.47) vs HR = 1.14 (0.98, 1.32), in overweight women. Conclusions We observed an increased risk of type 2 diabetes associated with mentally tiring work, used as a proxy of job demands. These observational results suggest the importance of taking into consideration the potential long-term metabolic impact of work-related stress for women working in a demanding environment. Increased support for such women should be investigated in intervention studies.