Significance The multiple-domain protein ZMYND8 is well known as a chromatin reader that recognizes methylated, acetylated, and/or mutated histones. Here we report that ZMYND8 is overexpressed in human ccRCC, and that it preferentially binds T487-phosphorylated EZH2. We show that in hypoxia-stimulated or von Hippel–Lindau–deficient cells, ZMYND8 binding of EZH2 is important for maintenance of EZH2 phosphorylation level, inhibition of PRC2 complex formation, and enhanced interaction between EZH2 and FOXM1. Our results reveal a reader function of ZMYND8 in recognizing a phosphorylation “code” on a nonhistone protein. Our findings also identify ZMYND8 binding as a facet of regulation and function of EZH2 phosphorylation in the Polycomb-dependent to -independent switch of EZH2/PRC2 activities.