AIMS/HYPOTHESIS: Oxidative stress plays a key role in the development of type 2 diabetes mellitus. We previously showed that the circulating antioxidant peroxiredoxin 4 (Prx4) is associated with cardiometabolic risk factors. We aimed to evaluate the association of Prx4 with type 2 diabetes risk in the general population. METHODS: We analysed data on 7,972 individuals from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study (49% men, aged 28-75 years) with no diabetes at baseline. Logistic regression models adjusted for age, sex, smoking, waist circumference, hypertension and family history of diabetes were used to estimate the ORs for type 2 diabetes. RESULTS: During a median follow up of 7.7 years, 496 individuals (288 men; 58%) developed type 2 diabetes. The median (Q1-Q3) Prx4 level was 0.84 (0.53-1.40) U/l in individuals who developed type 2 diabetes and 0.68 (0.43-1.08) U/l in individuals who did not develop type 2 diabetes. For every doubling of Prx4 levels, the adjusted OR (95% CI) for type 2 diabetes was 1.16 (1.05-1.29) in the whole population; by sex, it was 1.31 (1.14-1.50) for men and 1.03 (0.87-1.21) for women. Further adjustment for other clinical measures did not materially change the results. The addition of Prx4 to a validated diabetes risk score significantly improved the prediction of type 2 diabetes in men (p = 0.002 for reclassification improvement). CONCLUSIONS/INTERPRETATION: Our findings suggest that elevated serum Prx4 levels are associated with a higher risk of incident type 2 diabetes. For men, taking Prx4 into consideration can improve type 2 diabetes prediction over a validated diabetes risk score; in contrast, there is no improvement in risk prediction for women.