Background: Parenteral nutrition (PN) is often associated with liver dysfunction in the ICU, although other factors such as sepsis, acute heart failure (AHF), and hepatotoxic drugs can be equally present. The relative impact of PN on liver dysfunction in critically ill patients is largely unknown. Methods: We recorded the presence of pre-existing liver disturbances, AHF, sepsis, daily PN volume, and commonly used hepatotoxic drugs in adult ICU patients, together with daily aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT), alkalic phosphatase (AP), total bilirubin (TB), and INR values in patients with three or more PN treatment days. A linear mixed-effects model was used to assess the relative contribution of each liver parameter. Nutritional adequacy was defined as intake/needs. Results: We included 224 ICU patients with PN treatment lasting more than 3 days between 1 January 2017 and 31 December 2019. For AST, pre-existing liver disturbances (+180% ± 11%) and the presence of AHF (+75% ± 14%) were the main predictors of deterioration, whereas PN volume caused only a limited increase of 14% ± 1%/L. Similar results were observed for ALT. GGT, INR, and TB are mainly influenced by the presence of sepsis/septic shock and pre-existing liver disturbances, with no impact of PN or hepatotoxic drugs. Carbohydrate intake exceeded recommendations, and protein and lipid intake were insufficient in this study cohort. Conclusions: Liver test disturbances in ICU patients on PN are multifactorial, with sepsis and AHF having the highest influence, with only limited impact from PN and hepatotoxic drugs. Feeding adequacy can be improved.