Energy restriction affects circulating leptin and ghrelin concentrations.To investigate whether seafood consumption affects fasting leptin and ghrelin concentrations in addition to weight loss.In this 8-week dietary intervention, subjects (324 Icelandic, Spanish and Irish subjects, 20-40 years, BMI 27.5-32.5 kg/m(2)) were randomized to energy-restricted diets (-30%) of identical macronutrient composition but different amount of seafood: control (no seafood); lean fish (150 g cod, three times per week); fatty fish (150 g salmon, three times per week); EPA&DHA [daily docosahexaenoic (DHA)/eicosapentaenoic acid (EPA) capsules]. Anthropometric data, ghrelin, leptin, and insulin were measured at baseline and endpoint. Linear models investigated the effects of seafood on fasting leptin, ghrelin and insulin.Body weight (-5.2 +/- A 3.0 kg), leptin (-34.8%) and insulin (-13.5%) decreased, while ghrelin increased (5.6%) (all P < 0.001). According to linear models endpoint insulin was significantly lower in the EPA&DHA group (-16.4%, P = 0.025) compared to control, endpoint leptin in men was lower in the salmon group (-22.9%, P = 0.026), and the EPA&DHA group tended to have higher endpoint ghrelin (5.6%, P = 0.060), an effect seen only in women indicated by a significant gender x EPA&DHA interaction. Weight loss explained the effects of fatty seafood on leptin and ghrelin, but not insulin.Consumption of fatty seafood can modulate fasting insulin, ghrelin and leptin during an 8-week intervention. Effects are partly gender specific and are partly explained by weight loss. Consumption of lean fish does not affect circulating hormones in comparison to control. The most consistent effect on circulating hormones is mediated by weight loss.