Immunological effects of IL-21 on T, B and natural killer (NK) cells have been reported, but the role of IL-21 in GVHD remains obscure. Here, we demonstrate that morbidity and mortality of GVHD was significantly reduced after BMT with splenocytes from IL-21R(-/-) mice compared with those from wild type mice. To further confirm our observation, we generated a decoy receptor for IL-21. GVHD was again less severe in mice receiving BM cells transduced with the IL-21 decoy receptor than control mice These results suggest that IL-21 critically regulates GVHD, and that blockade of the IL-21 signal may represent a novel strategy for the prophylaxis for GVHD.