Disease-specific analysis of liver transplant survival benefit, which encompasses both pre-and posttransplant events, has not been reported. Therefore, we evaluated the effect of alcoholic liver disease (ALD) and hepatitis C virus (HCV) infection on waiting list mortality, posttransplant mortality, and the survival benefit of deceased donor liver transplantation using United States data from the Scientific Registry of Transplant Recipients on 38,899 adults placed on the transplant waiting list between September 2001 and December 2006. Subjects were classified according to the presence/absence of HCV and ALD. Cox regression was used to estimate waiting list mortality and posttransplant mortality separately. Survival benefit was assessed using sequential stratification. Overall, the presence of HCV significantly increased waiting list mortality, with a covariate-adjusted hazard ratio (HR) for HCV-positive (HCV؉) compared with HCV-negative (HCV؊) HR ؍ 1.19 (P ؍ 0.0001). The impact of HCV؉ was significantly more pronounced (P ؍ 0.001) among ALD-positive (ALD؉) patients (HR ؍ 1.36; P < 0.0001), but was still significant among ALD-negative (ALD؊) patients (HR ؍ 1.11; P ؍ 0.02). The contrast between ALD؉ and ALD؊ waiting list mortality was significant only among HCV؉ patients (HR ؍ 1.14; P ؍ 0.006). Posttransplant mortality was significantly increased among HCV؉ (versus HCV؊) patients (HR ؍ 1.26; P ؍ 0.0009), but not among ALD؉ (versus ALD؊) patients. Survival benefit of transplantation was significantly decreased among HCV؉ compared with HCV؊ recipients with model for end-stage liver disease (MELD) scores 9-29, but was significantly increased at MELD >30. ALD did not influence the survival benefit of transplantation at any MELD score. Conclusion: Except in patients with very low or very high MELD scores, HCV status has a significant negative impact on the survival benefit of liver transplantation. In contrast, the presence of ALD does not influence liver transplant survival benefit. (HEPATOLOGY 2009; 50:400-406.) See Editorial on Page 352 C irrhosis secondary to chronic hepatitis C viral (HCV) infection and alcoholic liver disease (ALD) are the two most common indications for liver transplantation in the United States. 1 In the past 25 years, expert opinion on the role of diagnosis in determining the outcome after liver transplantation has evolved with greater understanding of disease processes, and longer intervals of observation of larger patient cohorts. For example, in the first reports, ALD was thought to be a poor indication. 2 Subsequently, several accounts of successful transplantation and clinical recovery of alcoholic Abbreviations: ALD, alcoholic liver disease; CI, confidence interval; HCV, hepatitis C virus; MELD, model for end-stage liver disease; BMI, body mass index; HR, hazard ratio; UNOS, United Network for Organ Sharing.