AbstractBackground & AimsPatients with acute liver failure (ALF) awaiting liver transplantation (LT) may develop multiorgan failure, but organ failure does not impact waitlist prioritization. The aim of this study was to examine the impact of organ failure on waitlist mortality risk and post LT outcomes in patients with ALF.MethodsWe studied adults waitlisted for ALF in the United Network for Organ Sharing (UNOS) database (2002–2019). Organ failures were defined using a previously described Chronic Liver Failure modified sequential organ failure score assessment adapted to UNOS data. Regression analyses of the primary endpoints, 30‐day waitlist mortality (Competing risk), and post‐LT mortality (Cox‐proportional hazards), were performed. Latent class analysis (LCA) was used to determine the organ failures most closely associated with 30‐day waitlist mortality.ResultsAbout 3212 adults with ALF were waitlisted, for hepatotoxicity (41%), viral (12%) and unspecified (36%) etiologies. The median number of organ failures was three (interquartile range 1–3). Having ≥3 organ failures (vs. ≤2) was associated with a sub hazard ratio (HR) of 2.7 (95%CI 2.2–3.4)) and a HR of 1.5 (95%CI 1.1–2.5)) for waitlist and post‐LT mortality, respectively. LCA identified neurologic and respiratory failure as most impactful on 30‐day waitlist mortality. The odds ratios for both organ failures (vs. neither) were higher for mortality 4.5 (95% CI 3.4–5.9) and lower for delisting for spontaneous survival .5 (95%CI .4–.7) and LT .6 (95%CI .5–.7).ConclusionCumulative organ failure, especially neurologic and respiratory failure, significantly impacts waitlist and post‐LT mortality in patients with ALF and may inform risk‐prioritized allocation of organs.