Primary cutaneous anaplastic T-cell lymphoma, characterized by the CD30+ anaplastic large T cells, comprises the second most common group of cutaneous T-cell lymphoma. Little is known about the mechanisms of disease progression. Here we report that enhancer of zeste homolog 2 (EZH2), the catalytic subunit of polycomb repressive complex 2 that mediates histone H3 lysine 27 trimethylation, is overexpressed in CD30+ anaplastic cells in primary cutaneous anaplastic T-cell lymphoma and large-cell transformed cutaneous T-cell lymphoma. Silencing EZH2 or inhibiting its histone methyltransferase activity conferred increased apoptosis and G1 cell-cycle arrest in primary cutaneous anaplastic T-cell lymphoma cells in vitro and a xenograft model in vivo. This was mediated by the de-repression of thioredoxin-interacting protein, a major redox control molecule, and consequent formation of reactive oxygen species. Silencing thioredoxin-interacting protein abrogated reactive oxygen species accumulation in EZH2 suppressed cells and rescued cell growth disadvantage. Moreover, EZH2 suppression de-repressed C-X-C motif chemokine ligand 10 and facilitated the recruitment of effector CD4+ and CD8+ T cells into the tumor microenvironment via a C-X-C motif chemokine ligand 10/receptor 3 interaction. These results demonstrate a dual role for polycomb repressive complex 2-mediated epigenetic silencing in tumor progression and antitumor immunity in primary cutaneous anaplastic T-cell lymphoma, and provide a rationale for the pharmacologic inhibition of EZH2 activity in large-cell transformed cutaneous T-cell lymphoma.