BACKGROUND: The objective of this study was to investigate whether altering the fatty acid (FA) profile by omega-3 FA supplementation affects inflammatory response and systemic disease sequelae in severe acute pancreatitis. METHODS: Forty severe acute pancreatitis patients were enrolled and randomly assigned to receive parenteral nutrition (PN) for 5 days in a double-blind manner. Patients received PN with identical amounts of amino acids (1.25 g/kg/d), glucose (3 g/kg/d), and fat (1 g/kg/d) but different lipid compositions: the control group received a soybean oil (SO; Lipovenos 20%; Fresenius, Germany)-based fat solution and the omega-3 FA group was supplemented with 0.15 - 0.2 g/kg/d fish oil (FO; Omegaven 10%; Fresenius, Germany). Serum concentrations of eicosapentaenoic acid (EPA), interleukin-6, C-reactive protein (CRP), white blood cell count, and routine respiratory and renal parameters were measured before PN, and again on day 6 after starting PN. Outcomes such as infection morbidity, mortality, intensive care unit time, and length of hospital stay were recorded. RESULTS: Patients treated with FO had a significantly higher EPA concentration (P < .01), lower CRP level (P < .05), and better oxygenation index (P < .05) after 5 days of PN. Moreover, the number of days of continuous renal replacement therapy (CRRT) in the omega-3 FAs group was significantly less than that in the control group (P < .05). CONCLUSIONS: PN supplemented with omega-3 FAs diminishes the hyperinflammatory response by the EPA increase and the proinflammatory cytokine decrease in severe acute pancreatitis. This, together with improved respiratory function and shortened CRRT time, suggests that the systemic response to pancreatic and organ injury is attenuated.