Merkel cell carcinoma (MCC) is an aggressive skin cancer for which Merkel cell polyomavirus (MCPyV) integration and expression of viral oncogenes small T and Large T have been identified as major oncogenic determinants. Recently, a component of the PRC2 complex, the histone methyltransferase EZH2 that induces H3K27 tri-methylation as a repressive mark has been proposed as a potential therapeutic target in MCC. Since divergent results have been reported for the levels of EZH2 and H3K27me3, we analyzed these factors in a large MCC cohort to identify the molecular determinants of EZH2 activity in MCC and to establish MCC cell lines sensitivity to EZH2 inhibitors. Immunohistochemical expression of EZH2 was observed in 92\% of MCC tumors (156/170) with higher expression levels in virus-positive than virus-negative tumors (p= 0.026). For the latter, we demonstrated overexpression of EZHIP, a negative regulator of the PRC2 complex. In vitro, ectopic expression of the Large T antigen in fibroblasts led to the induction of EZH2 expression while knockdown of T antigens in MCC cell lines resulted in decreased EZH2 expression. EZH2 inhibition led to selective cytotoxicity on virus-positive MCC cell lines. This study highlights the distinct mechanisms of EZH2 induction between virus-negative and -positive MCC.