Animal studies suggest that receptor for advanced glycation end products (RAGE)–dependent mechanisms contribute to acetaminophen‐induced liver damage. We examined whether circulating levels of soluble receptor for advanced glycation end products (sRAGE) or RAGE ligands, including extracellular newly identified receptor for advanced glycation end products binding protein (EN‐RAGE), high‐mobility group box 1 (HMGB1), and Nε‐(Carboxymethyl)lysine adducts (CML), could aid in prognostication after an acetaminophen overdose. Sixty well‐characterized acetaminophen‐related acute liver failure (ALF) patients (30 spontaneous survivors and 30 patients who underwent transplantation and/or died) who were enrolled in the National Institutes of Health–sponsored Acute Liver Failure Study Group, were matched by age, met standard criteria for encephalopathy, and had an international normalized ratio > 1.5 were retrospectively studied. HMGB1, EN‐RAGE, CML, and sRAGE were detected by enzyme‐linked immunosorbent assay methods in sera from ALF patients and 30 healthy controls. Levels of sRAGE, EN‐RAGE, and HMGB1 (but not CML) were significantly greater (P < 0.001) in ALF patients versus normal controls. The levels of sRAGE, HMGB1, and EN‐RAGE were significantly higher (P = 0.03, P < 0.01, and P = 0.03) in patients with a systemic inflammatory response syndrome (SIRS) score > 2 versus patients with a SIRS score ≤ 2. Nevertheless, only sRAGE levels were significantly higher in patients who underwent transplantation and/or died versus spontaneous survivors (P < 0.001), and they were positively associated with conventional markers of liver disease severity. Multivariate logistic regression identified an encephalopathy grade > 2 as an independent predictor of an adverse outcome on admission (odds ratio, 13; 95% confidence interval, 2.3‐73; P < 0.001). The RAGE‐ligand axis may interfere with liver regeneration and should be a promising objective for further research. Liver Transpl 21:847‐854, 2015. © 2015 AASLD.