Upon interaction with B7 homolog 1, programmed death-1 (PD-1) transmits a critical coinhibitory signal to T cells to negatively regulate immune responses. By extensively searching the genomic database with the IgV region of PD-1, we identified a homolog and named it PD-1 homolog (PD-1H). PD-1H is broadly expressed on the cell surface of hematopoietic cells and could be further upregulated on CD4(+) and CD8(+) T cells following activation. We have generated an mAb against PD-1H, which strikingly prevents acute graft-versus-host disease in semi- and fully allogeneic murine models, leading to full chimerism following treatment. Graft-versus-host disease remains a primary hindrance to successful allogeneic hematopoietic cell transplantation therapy for the treatment of hematologic malignancy. Therefore, manipulation of PD-1H function may provide a new modality for controlling T cell responses to allogeneic tissues in transplant medicine.