In this study, we show that Enhancer of Zeste Homolog 2 (EZH2) inhibition by valemetostat DS3201 (DS) induced the lytic reactivation of Kaposi sarcoma associated herpesvirus (KSHV) from latency in BC3 and BCBL-1 primary effusion lymphoma (PEL) cells and unveil new molecular mechanisms involved in this effect. Here, EZH2 is linked to primary effusion lymphoma.