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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is often complicated by alloreactive donor T-cell-mediated graft-versus-host disease (GvHD). The major polyphenol of green tea, epigallocatechin-3-gallate (EGCG), is an inhibitor of both DNA methyltransferase 1 (DNMT1) and signal transducer and activator of transcription 1 (STAT1), which are essential for induction of GvHD. Thus, in this report, we examine if in vivo administration of EGCG mitigates GvHD in several different animal models. While we concede that refinement of EGCG treatment might result in GvHD prevention, our results suggest that EGCG treatment might not be an effective therapy against GvHD in the clinic.