The up-to-seven (Up-to-7) criteria [with 7 being the sum of the size and number of tumors for any given hepatocellular carcinoma (HCC)] have been recently proposed to identify potential candidates for liver transplantation (LT) among patients exceeding the Milan criteria. The aim of this study was to compare the ability of the available pathologic staging systems (the Milan, University of California San Francisco, and Up-to-7 criteria) to predict recurrence. A study population of 479 HCC transplanted patients was identified from prospectively collected databases at Mount Sinai Medical Center (New York, NY) and the University of Padua (Padua, Italy). The best pathologic staging system was identified with log rank, proportion separation index (PSEP), and Cox analyses. Pathologic tumor characteristics (tumor number, tumor size, sum of diameters, macroscopic and microscopic vascular invasion, and grading) were then tested by univariate and multivariate Cox analyses in the prognostic subgroups within and beyond the calculated criteria. The Up-to-7 criteria performed as the best pathologic staging system, the calculated 1-, 3-, and 5-year recurrence probabilities being 4%, 8%, and 14% within the criteria (n Ο 355) and 22%, 45%, 51% beyond the criteria (n Ο 124; P Ο½ 0.0001) and the calculated PSEP being 0.27 (95% confidence interval Ο 0.23-0.31). In multivariate analysis, only biological variables (vascular invasion and tumor grade) significantly predicted recurrence beyond the Up-to-7 criteria. A 3-stage pathologic staging system with a potential to be applied in the preoperative setting was thus created: within the Up-to-7 criteria (recurrence rate Ο 8%), beyond the Up-to-7 criteria without macrovascular invasion and poorly differentiated grade (recurrence rate Ο 24%), and beyond the Up-to-7 criteria with macrovascular invasion and/or poorly differentiated grade (recurrence rate Ο 45%). In conclusion, HCC patients within the pathologic Up-to-7 criteria were associated with a low risk of recurrence after LT. Beyond these criteria, however, a significant proportion of patients with a good HCC biological profile had an acceptable risk of recurrence.