Cholestatic liver dysfunction (CLD) and biliary sludge often occur during critical illness and are allegedly aggravated by parenteral nutrition (PN). Delaying initiation of PN beyond day 7 in ICU (late-PN) accelerated recovery as compared with early initiation of PN (early-PN). However, the impact of nutritional strategy on biliary sludge and CLD has not been fully characterized. This was a preplanned subanalysis of a large RCT of early-PN versus late-PN (n=4640). In all patients plasma bilirubin (daily) and liver enzymes (ALT/AST/GGT/ALP; twice weekly; n=3216) were quantified. In a random predefined subset of patients also plasma bile acids (BAs) were quantified at baseline and on days 3, 5 and last ICU-day (n=280). Biliary sludge was ultrasonographically evaluated on ICU-day 5 (n=776). From day 1 after randomization until the end of the 7-day intervention window, bilirubin was higher in the late-PN than in the early-PN group (p<0.001). In the late-PN group, as soon as PN was started on day 8, bilirubin fell and the two groups became comparable. Maximum levels of GGT, ALP and ALT were lower in the late-PN group (p<0.01). Glycine/taurine-conjugated primary BAs increased over time in ICU (p<0.01), similarly for the two groups. Fewer patients in the late-PN than in the early-PN group developed biliary sludge on day 5 (37% vs 45%; p=0.04). In conclusion, tolerating substantial caloric deficit by withholding PN until day 8 of critical illness increased plasma bilirubin but reduced the occurrence of biliary sludge and lowered GGT, ALP and ALT. These results suggest that hyperbilirubinemia during critical illness does not necessarily reflect cholestasis and instead may be an adaptive response that is suppressed by early-PN. (Hepatology 2013;).