Chronic graft-versus-host disease (cGVHD) is a common cause of morbidity and mortality in allogeneic bone marrow transplantation (alloBMT). However, effective strategies for the treatment of cGVHD have not been established. In this study, we examined the therapeutic utility of modified dendritic cells (DCs) with a greater capacity to regulate immune responses than previously known tolerogenic DCs, regulatory DCs (DC(regs)), in the major histocompatibility complex-compatible, and multiple minor histocompatibility antigen-incompatible model of cGVHD in alloBMT. Treatment of the recipient mice after alloBMT with the recipient-type DC(regs) led to greater suppression of the incidence and severity of cutaneous cGVHD than rapamycin, whereas treatment with the recipient-type mature DCs promoted the pathogenesis. Analysis of the recipient mice suggested that the protective effect of the recipient-type DC(regs) involved the peripheral generation of alloreactive CD4(+)CD25(+)Foxp3(+)regulatory T (T(R)) cells from donor-derived CD4(+)CD25(-)Foxp3(-) T cells. Thus, immunotherapy with DC(regs) is a promising strategy for the treatment of cGVHD in alloBMT mediated through the induction of a dominant tolerance involving CD4(+)CD25(+)Foxp3(+) T(R) cells.