Background: The role of some nutritional factors and hypocaloric diets on oxidative balance is a matter of debate, especially related to the prevention and treatment of obesity and co-morbidities. Aim of the study: The aim was to investigate the antioxidant capacity of different energy restricted diets in the treatment of obesity, paying emphasis to the effect of incorporating omega-3 fatty acids with or without other seafood components. Methods: The study was a randomized 8-weeks parallel intervention trial prescribed to lose weight, which was implemented in 276 subjects aged 31.4 ± 5.4 y.o. following four different balanced hypocaloric diets (TEE-30%): fish-restricted (control), cod and salmon based diets and DHA+EPA supplemented administration. At baseline (day 0) and at the end of the trial (day 56), anthropometry, dietary intake, erythrocyte membrane fatty acid content, circulating malondialdehyde (MDA) and plasma antioxidant status (AOP) were determined. Results: Overall, percent weight loss was -5.8 ± 3.2% (P < 0.001) and the AOP statistically increased after the energy restriction period (P = 0.015), basically due to the seafood-based diets. In contrast, MDA statistically only decreased (P = 0.026) after the cod-based diet intake with no changes after the other nutritional treatments. In fact, the cod-based intervention statistically decreased oxidative stress when expressed as the MDA/AOP ratio (P = 0.006). Conclusions: A moderate calorie-restricted cod-based diet was found as a useful strategy to lose weight, which was accompanied by a specific improvement on oxidative stress markers. The low saturated fat content and the seafood protein source of this diet may be important factors involved in these findings.