Functional outcomes for long-term survivors of acute liver failure (ALF) are not well characterized. The aim of this prospective study was to determine health-related quality of life in long-term adult ALF survivors. Acute Liver Failure Study Group registry participants completed the Centers for Disease Control and Prevention Health-Related Quality of Life 14 and Short Form 36 (SF-36) questionnaires at 1- and/or 2-year follow-up study visits. Responses were compared among ALF subgroups and to those for available general US population controls. Among the 282 adult ALF patients, 125 had undergone liver transplantation (LT), whereas 157, including 95 acetaminophen overdose (APAP) patients and 62 non-APAP patients, were spontaneous survivors (SSs). APAP SS patients reported significantly lower general health scores and more days of impaired mental and physical health, activity limitations due to poor health, pain, depression, and anxiety in comparison with the other groups (P ≤ 0.001). There were no significant differences in coma grade or in the use of mechanical ventilation or intracranial pressure monitoring among the patient groups during their ALF hospitalization, but APAP SSs had significantly higher rates of psychiatric disease and substance abuse (P < 0.001). In comparison with the general US population, a greater proportion of the combined SS patients reported fair or poor health and ≥14 days of impaired physical/mental health and activity limitations due to poor health. In addition, a greater proportion of LT recipients reported ≥14 days of impaired physical/mental health. Similar results were observed with the SF-36 across the 3 ALF subgroups and in comparison with population controls. In conclusion, long-term adult survivors of ALF reported significantly lower quality of life scores than US population controls. Furthermore, APAP SS patients reported the lowest quality of life scores, possibly because of higher rates of premorbid psychiatric and substance abuse disorders. Liver Transpl 19:991-1000, 2013. © 2013 AASLD. © 2013 American Association for the Study of Liver Diseases.