The effect of fat contained in total parenteral nutrition (TPN) regimens on the immune system is controversial. The purpose of our study was to examine whether the synthesis of tumor necrosis factor (TNF), a macrophage-derived protein with several immunomodulating effects, is influenced by the duration of TPN. We studied 20 patients on glucose- and fat-based TPN with lipid emulsions containing long-chain triglycerides (LCTs). Ten of our patients received TPN for 15 days (group A) and the other 10 for 30-40 days (group B). We measured TNF production by phytohemagglutinin- and endotoxin-stimulated peripheral blood mononuclear cells before and after TPN via enzyme-linked immunosorbent assay. The production of TNF before and after TPN was similar in group A but significantly (p less than 0.01) elevated in group B after long-term TPN. Therefore, long-term TPN containing LCTs may increase TNF production, and this may be the result of an immunomodulating effect of fat.