Background <p>To investigate the adverse events, diagnostic yield, and therapeutic implications of liver biopsy in intensive-care-unit (ICU) patients.</p> Methods <p>Retrospective observational multicenter cohort study. Consecutive adults admitted to any of the four participating ICUs in France between January 1, 2006 and March 1, 2023, and who had a liver biopsy during the ICU stay were included.</p> Results <p>We included 139 patients (median age, 52 years; 69% male) biopsied via the transjugular (<i>n</i> = 97), percutaneous (<i>n</i> = 30), or laparoscopic (<i>n</i> = 1) route (missing data <i>n</i> = 11). The liver parenchyma was evaluable in 137/139 (99%) patients, who had 187 histological diagnoses in total. The pathological diagnoses matched the pre-biopsy diagnostic hypotheses in 83 (60%) patients. The most common were chronic or acute-on-chronic liver disease (<i>n</i> = 78, 56%), malignancy (<i>n</i> = 27, 19%), and infectious disease (<i>n</i> = 12, 9%). Among other diagnoses (<i>n</i> = 17, 12%), drug toxicity and biliary diseases predominated. The liver biopsy had therapeutic implications for 80 (58%) patients, among whom 66 (82%) received a new treatment, 7 (9%) were continued on empirically initiated treatment, and 7 (9%) were taken off the previous treatment. WHO grade 3–4 bleeding developed in 10 (7%) patients and was fatal in 2 patients. Higher severity scores, higher urea level, and absence of cirrhosis were associated with a greater risk of bleeding complications. Day-90 survival was not significantly different between the groups with vs. without therapeutic implications of the biopsy.</p> Conclusions <p>In ICU patients, liver biopsy provides a wide range of diagnoses and guides treatment decisions. However, the risk of potentially fatal bleeding is a major concern. We identified risk factors for bleeding.</p>