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We aimed to determine whether combining serum alpha-fetoprotein (AFP) level with hepatocellular carcinoma (HCC) tumor burden would allow better stratification of posttransplant survival for patients with HCC undergoing liver transplantation. Adjusting for donor and recipient characteristics, we calculated the risk of posttransplant mortality associated with serum AFP level or HCC tumor burden for all first-time adult liver transplants performed in the United States between 2002 and 2011 (n = 45,267). Serum AFP level, rather than tumor burden, was the tumor characteristic most strongly associated with posttransplant survival. Although recipients with HCC and a serum AFP level ≤ 15 ng/mL at the time of transplantation had no excess posttransplant mortality [adjusted hazard ratio (AHR) = 1.02, 95% confidence interval (CI) = 0.93-1.12], patients with a serum AFP level of 16 to 65 ng/mL (AHR = 1.38, 95% CI = 1.23-1.54), patients with a serum AFP level of 66 to 320 ng/mL (AHR = 1.65, 95% CI = 1.45-1.88), and patients with a serum AFP level > 320 ng/mL (AHR = 2.37, 95% CI = 2.06-2.73) had progressively worse posttransplant mortality in comparison with recipients without HCC. Patients with a tumor burden exceeding the Milan criteria (who are usually excluded from transplantation) had excellent posttransplant survival if their serum AFP level was 0 to 15 ng/mL (AHR = 0.97, 95% CI = 0.66-1.43). In contrast, patients within the Milan criteria (who are routinely considered to be transplant candidates) had poor survival if their serum AFP level was substantially elevated (for a serum AFP level ≥ 66 ng/mL, AHR = 1.93, 95% CI = 1.74-2.15). Changes in serum AFP level while patients were on the waiting list corresponded closely to changes in posttransplant mortality. In conclusion, the absolute serum AFP level and changes in the serum AFP level strongly predict posttransplant survival independently of the tumor burden. We hope that these data, in combination with other factors, can be used to inform future studies and ongoing discussions aimed at improving the eligibility criteria for liver transplantation for patients with HCC. Liver Transpl 19:634–645, 2013. © 2013 AASLD.