ABSTRACTBackground and Objective:Resolution of parenteral nutrition (PN)–associated jaundice has been reported in children given a reduced dose of intravenous fat using a fish oil–derived lipid emulsion. The aim of the present study was to examine the effect on PN‐associated jaundice of changing from a soybean oil–derived lipid to a mixed lipid emulsion derived from soybean, coconut, olive, and fish oils without reducing the total amount of lipid given.Methods:Retrospective cohort comparison examining serum bilirubin during 6 months in children with PN‐associated jaundice who changed to SMOFlipid (n = 8) or remained on Intralipid (n = 9).Results:At entry, both groups received most of their energy as PN (SMOFlipid 81.5%, range 65.5–100 vs Intralipid 92.2%, range 60.3–100; P = 0.37). After 6 months, both tolerated increased enteral feeding but still received large proportions of their energy as PN (SMOFlipid 68.4%, range 36.6–100 vs Intralipid 50%, range 37.6–76; P = 0.15). The median bilirubin at the outset was 143 μmol/L (range 71–275) in the SMOFlipid group and 91 μmol/L (range 78–176) in the Intralipid group. After 6 months, 5 of 8 children in the SMOFlipid and 2 of 9 children in the Intralipid group had total resolution of jaundice. The median bilirubin fell by 99 μmol/L in the SMOFlipid group but increased by 79 μmol/L in the Intralipid group (P = 0.02).Conclusions:SMOFlipid may have important protective properties for the liver and may constitute a significant advance in PN formulation. Randomised trials are needed to study the efficacy of SMOFlipid in preventing PN liver disease.