Salt sensitivity (SS) is associated with increased cardiovascular risk in type-2 diabetes mellitus (T2-DM) patients due to an increase in renal oxidation. ω-3 polyunsaturated fatty acids have shown antioxidant effects, but a typical Western diet has limited content of them. In particular, ω-3 PUFAs are able to activate Nrf-2 (nuclear factor erythroid 2-related factor) to prevent DM-related complications by mitigating oxidative stress. Therefore, we hypothesized that eicosapentaenoic acid (EPA, ω-3) modulates SS in T2-DM rats, by decreasing renal oxidative stress via Nrf-2 activation, and enhancing the anti-inflammatory response via IL-6 modulation. 3-months-old male rats (n=40) were fed with a normal Na-diet (NNaD) and randomly selected into 4 groups: i. healthy Wistar rats, non-diabetic rats (Wi), ii. diabetic control (eSS), iii. arachidonic acid-treated eSS (ω-6) (AA), iv. EPA-treated eSS (ω-3) (EPA). After one year, rats were placed in metabolic cages for 7 days and fed with a NNaD and followed by a 7 days period with high Na-diet (HNaD). Systolic blood pressure (SBP), body weight (BW), serum interleukin-6 (IL-6) and reactive oxygen species (ROS) levels were determined at the end of each 7-day period. Glycated hemoglobin (HbA1c), triglycerides (TAG), creatinine and cholesterol (Chol) were determined. ROS levels and Nrf-2 expression in kidney lysates were also assayed. Histological changes were evaluated. T-test or ANOVA were used for statistical analysis. Following HNaD, SBP increased in both control eSS and AA groups, but not in EPA and Wi groups. However, HbA1c remained unchanged by the treatments, suggesting that the beneficial effect observed was independent of HbA1c level. IL-6 levels were higher in eSS and AA, but it remained unaltered in EPA and Wi rats following HNaD diet. Interestingly, EPA protected against serum ROS in rats fed the HNaD, whereas AA did not. In kidney lysates, ROS decreased significantly in EPA compared to eSS, and consistently, Nrf-2 expression was higher compared to AA and eSS. Diabetic rats presented focal segmental sclerosis, adherence to Bowman capsule and mild to moderate interstitial fibrosis. EPA and AA treatment prevented the kidney damage. An adequate ω3:ω6 prevents SS in diabetic rats, by a mechanism independent of glucose metabolism but associated to the prevention of renal oxidative stress generation. These data suggest that EPA antioxidant properties may prevent the development of hypertension or kidney damage.