Previous studies on loco-regional therapy (LRT) and alpha-fetoprotein (AFP) in predicting outcome after liver transplant (LT) for hepatocellular carcinoma (HCC) have shown inconsistent results. We analyzed the OPTN database in Region 5 from January 2004 to January 2009 and performed univariate and multivariate analysis of 11 pre-transplant recipient and donor variables in 1074 patients with HCC meeting Milan criteria to detect association with post-LT tumor recurrence or mortality. Mean waitlist time was 438 d. The 1- and 5-yr post-LT survival was 91.1% and 71.1%, respectively. In multivariate analysis, AFP before LT was the only predictor of HCC recurrence. The association between AFP and HCC recurrence was observed only in the subgroup receiving LRT but not in the subgroup without LRT. Predictors of mortality in multivariate analysis were HCC recurrence, Donor Risk Index, last AFP before LT, and MELD score. AFP before LT was the strongest predictor of post-transplant HCC recurrence or death in multivariate analysis. In conclusion, in Region 5 with prolonged waitlist time, high AFP was the only pre-transplant variable predicting post-transplant tumor recurrence and mortality for HCC meeting Milan criteria. Our results also supported the importance of the effects of LRT on AFP in predicting prognosis.