Background & aims: Acute conditions such as trauma and inflammation disturb glucose and lipid homeostasis. Enteral and parenteral nutrition including omega-3 fatty acids (omega-3 FA) have been shown to modulate the host immune response to inflammation. However, their impact on lipid and glucose metabolism during the postoperative period is currently unknown. Methods: We prospectively studied 44 patients suffering from carcinoma of the gastrointestinal tract or the pancreas. After surgery, all patients received total parenteral nutrition (TPN) for 5 days with either soybean oil (SO) or fish oil (FO)+SO emulsions in a double-blinded manner. Results: With respect to plasma levels of lipids and lipoproteins, we found that total cholesterol and low density lipoprotein (LDL)-cholesterol increased in both groups with LDL-cholesterol being significantly higher in the SO group compared to the SO+FO group at the third and fourth postoperative day. High density lipoprotein (HDL)-cholesterol remained unchanged. Triglycerides (TGs) and very low-density lipoprotein (VLDL)-cholesterol increased during TPN. TG values were similar in both groups, while VLDL levels rose earlier under SO+FO and reached higher values compared to SO. Blood glucose levels normalized to the insulin doses applied did not differ significantly between the two groups. However, in the SO group blood glucose levels significantly fell over time while this was not the case in the SO+FO group. Conclusions: Our data demonstrate that in postoperative patients the TG- and VLDL-lowering effects of omega-3 FA are offset by acute regulatory changes during the acute-phase-response and there is evidence for a subtle impairment in glycemic control under SO+FO.