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Human cytomegalovirus (CMV) infection has been reported to compromise liver transplantation (LT) outcomes. Recent studies have shown that CMV has a beneficial oncolytic ability. The aim of this study was to investigate the impact of CMV on tumor recurrence in patients with hepatocellular carcinoma (HCC) who underwent liver transplantation (LT). This retrospective study enrolled 280 HCC patients with LT at our institute between January 2005 and January 2016. Their relevant demographic characteristics, pre- and post-LT conditions, and explant histology were collected. A CMV pp65 antigenemia assay was performed weekly following LT to identify CMV infection. A total of 121 patients (43.2%) were CMV antigenemia-positive and 159 patients (56.8%) were negative. A significantly superior five-year recurrence-free survival was observed among CMV antigenemia-positive patients compared with the CMV-negative group (89.2% vs. 79.9%, p = 0.049). There was no significant difference in overall survival between the positive and negative CMV antigenemia groups (70.2% vs. 75.3%, p = 0.255). The major cause of death was HCC recurrence in CMV antigenemia-negative patients (51.3%), whereas more CMV antigenemia-positive patients died due to other bacterial or fungal infections (58.3%). In the multivariate analysis, the independent risk factors for tumor recurrence included positive CMV antigenemia (p = 0.042; odds ratio (OR) = 0.44; 95% confidence interval (CI) = 0.20-0.97), microscopic vascular invasion (p = 0.001; OR = 3.86; 95% confidence interval (CI) = 1.78-8.36), and tumor status beyond the Milan criteria (p = 0.001; OR = 3.69; 95% CI = 1.77-7.71). In conclusion, in addition to the well-known Milan criteria, human CMV is associated with a lower HCC recurrence rate after LT. However, this tumor suppressive property does not lead to prolonged overall survival, especially in severely immunocompromised patients who are vulnerable to other infections. [ABSTRACT FROM AUTHOR]