The human leukocyte antigen (HLA)-DR expression on monocytes and plasma Interleukin (IL)-10 levels are key indicators of immune response during the acute phase of severe acute pancreatitis (SAP). We designed a pilot study to investigate whether omega-3 fatty acids (FAs) supplemented parenteral nutrition (PN) could improve immune response in SAP patients. Fifty-six SAP patients were enrolled (28 patients in each group) and received isocaloric and isonitrogenous parenteral nutrition, providing 1.0 g/kg/day standard soybean-oil based fat (omega-6 FAs group) or 0.8 g/kg/day soybean oil +0.2 g/kg/day omega-3 FAs based fat (omega-3 FAs group). IL-10, HLA-DR and the ratio of CD4(+) to CD8(+) were determined before PN treatment and on day 6 after starting PN. The infection and surgery rates were recorded until hospital discharge. A significant IL-10 increase was associated with the administration of omega-3 FAs (p = 0.04, vs omega-6 FAs group). Monocyte HLA-DR expression improved in both groups after 5 days of PN treatment. This increase was significantly higher in the omega-3 FAs group compared to omega-6 FAs (p = 0.01). There was no significant difference of CD4(+)/CD8(+), infection and surgery rates between the two groups. In conclusion, omega-3 FAs supplemented PN can elevate the IL-10 level and HLA-DR expression in SAP patients. A larger trial is required to see whether omega-3 FAs supplemented PN treatment in SAP patients would result in better clinical outcomes than omega-6 FAs.