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Although experimental evidence has indicated that ischemia-reperfusion (I/R) injury of the liver stimulates growth of micrometastases and adhesion of tumor cells, the clinical impact of I/R injury on recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) has not been fully investigated. To study this issue, we conducted a retrospective review of the medical records of 391 patients from two transplant centers who underwent LT for HCC. Ischemia times along with other tumor/recipient variables were analyzed as risk factors for recurrence of HCC. Subgroup analysis focused on patients with HCC who had pathologically proven vascular invasion (VI) because of the associated increased risk of micrometastasis. Recurrence occurred in 60 patients (15.3%) with median time to recurrence of 0.9 years (range, 40 days-4.6 years). Cumulative recurrence curves according to cold ischemia time (CIT) at 2-hour intervals and warm ischemia time (WIT) at 10-minute intervals showed that CIT >10 hours and WIT >50 minutes were associated with significantly increased recurrence (P = 0.015 and 0.036, respectively). Multivariate Cox's regression analysis identified prolonged cold (>10 hours; P = 0.03; hazard ratio [HR] = 1.9) and warm (>50 minutes; P = 0.003; HR = 2.84) ischemia times as independent risk factors for HCC recurrence, along with tumor factors, including poor differentiation, micro- and macrovacular invasion, exceeding Milan criteria, and alpha-fetoprotein >200 ng/mL. Prolonged CIT (P = 0.04; HR = 2.24) and WIT (P = 0.001; HR = 5.1) were also significantly associated with early (within 1 year) recurrence. In the subgroup analysis, prolonged CIT (P = 0.01; HR = 2.6) and WIT (P = 0.01; HR = 3.23) were independent risk factors for recurrence in patients with VI, whereas there was no association between ischemia times and HCC recurrence in patients with no VI. Conclusion: Reducing ischemia time may be a useful strategy to decrease HCC recurrence after LT, especially in those with other risk factors. (Hepatology 2015;61:895–904)