CD30, a TNFR family member, is expressed on activated CD4+ and CD8+ T cells and B cells and is a marker of Hodgkin's lymphoma; its ligand, CD30L (CD153) is expressed by activated CD4+ and CD8 + T cells, B cells, and macrophages. Signaling via CD30 can lead to proliferation or cell death. CD30-deficient (-/-) mice have impaired thymic negative selection and increased autoreactivity. Although human alloreactive T cells preferentially reside within the CD30+ T cell subset, implicating CD30 as a regulator of T cell immune responses, the role of CD30/CD153 in regulating graft-vs-host disease (GVHD) has not been reported. We used a neutralizing anti-CD153 mAb, CD30-/- donor mice, and generated CD153-/- recipient mice to analyze the effect of CD30/CD153 interaction on GVHD induction. Our data indicate that the CD30/CD153 pathway is a potent regulator of CD4+, but not CD8+, T cell-mediated GVHD. Although blocking CD30/CD153 interactions in vivo did not affect alloreactive CD4+ T cell proliferation or apoptosis, a substantial reduction in donor CD4+ T cell migration into the gastrointestinal tract was readily observed with lesser effects in other GVHD target organs. Blockade of the CD30/CD153 pathway represents a new approach for preventing CD4+ T cell-mediated GVHD.