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Regulatory T (Treg) cells expressing the transcription factor FOXP3 play a pivotal role in maintaining immunologic self-tolerance. We and others have shown previously that EZH2 is recruited to the FOXP3 promoter and its targets in Treg cells. To further address the role for EZH2 in Treg cellular function, we have now generated mice that lack EZH2 specifically in Treg cells (EZH2(Δ/Δ)FOXP3(+)). We find that EZH2 deficiency in FOXP3(+) T cells results in lethal multiorgan autoimmunity. We further demonstrate that EZH2(Δ/Δ)FOXP3(+) T cells lack a regulatory phenotype in vitro and secrete proinflammatory cytokines. Of special interest, EZH2(Δ/Δ)FOXP3(+) mice develop spontaneous inflammatory bowel disease. Guided by these results, we assessed the FOXP3 and EZH2 gene networks by RNA sequencing in isolated intestinal CD4(+) T cells from patients with Crohn's disease. Gene network analysis demonstrates that these CD4(+) T cells display a Th1/Th17-like phenotype with an enrichment of gene targets shared by FOXP3 and EZH2. Combined, these results suggest that the inflammatory milieu found in Crohn's disease could lead to or result from deregulation of FOXP3/EZH2-enforced T cell gene networks contributing to the underlying intestinal inflammation.