Natural killer (NK)–cell alloreactivity is exploited in bone marrow transplantation to improve clinical outcome. Likewise, in solid organ transplantation, it has been recently shown that recipient NK cells may limit alloreactive T-cell responses through their capacity to prevent the persistence of graft-derived allogeneic dendritic cells (DCs). In a model of CD4⁺ T cell–mediated allogeneic skin graft rejection, we show that the absence of host NK-cell alloreactivity was characterized by enhanced expansion of alloreactive effector T lymphocytes, including Th2 cells, and massive eosinophilic infiltrates in the rejected tissues. In CD8⁺ T cell–deficient C57BL/6 (H-2^b) recipients injected with allogeneic BALB/c (H-2^d) DCs, we demonstrated that NK cells expressing the H-2D^d-specific Ly49D activating receptor were implicated in the regulation of alloreactive CD4⁺ T-cell responses. Moreover, we showed that Ly49D⁺ CD127⁻ NK cells were recruited within DC draining lymph nodes and rapidly eliminated allogeneic H-2^d DCs through the perforin pathway. In normal mice, we further demonstrated that NK cells by quickly eliminating allogeneic DCs strongly inhibited alloreactive CD8⁺ T-cell responses. Thus, NK cells act as early regulators of alloreactive T-cell priming in allotransplantation through their capacity to kill allogeneic DCs in draining lymph nodes.