Malignant melanoma from the conjunctiva (CM) is definitely an uncommon but potentially deadly disorder. Many malignancies show an elevated activity from the epigenetic modifier enhancer of zeste homolog 2 (EZH2). We studied whether EZH2 is expressed in CM, and whether it might be a target for therapy within this malignancy. Immunohistochemical analysis demonstrated that EZH2 protein expression was absent in normal conjunctival melanocytes and first acquired melanosis, while EZH2 was highly expressed in 13 (50%) of 26 primary CM and 7 (88%) of eight lymph node metastases. Elevated expression was positively connected with tumor thickness (p =.03). Next, we targeted EZH2 with specific inhibitors (GSK503 and UNC1999) or depleted EZH2 by stable shRNA knockdown in three primary CM cell lines. Both medicinal and genetic inactivation of EZH2 inhibited cell growth and colony formation and influenced EZH2-mediated gene transcription and cell cycle profile in vitro. The tumor suppressor gene p21/CDKN1A was especially upregulated in CM cells after EZH2 knockdown in CM cells. Furthermore, the strength of GSK503 against CM cells was monitored in zebrafish xenografts. GSK503 profoundly attenuated tumor development in CM xenografts in a well-tolerated concentration. Our results indicate that elevated amounts of EZH2 are highly relevant to CM tumourigenesis and progression, which EZH2 can become a possible therapeutic target for patients with CM. ? 2018 The Authors. The Journal of Pathology printed by John Wiley & Sons Limited with respect to Pathological Society of effective Britain and Ireland.