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In this study, we investigated the role of V[Alpha]14 natural killer T (NKT) cells in transplant immunity. The ability to reject allografts was not significantly different between wild-type (WT) and V[Alpha]14 NKT cell-deficient mice. However, in models in which tolerance was induced against cardiac allografts by blockade of lymphocyte function-associated antigen-1/intercellular adhesion molecule-1 or CD28/B7 interactions, long-term acceptance of the grafts was observed only in WT but not V[Alpha]14 NKT cell-deficient mice. Adoptive transfer with V[Alpha]14 NKT cells restored long-term acceptance of allografts in V[Alpha]14 NKT cell-deficient mice. The critical role of V[Alpha]14 NKT cells to mediate immunosuppression was also observed in vitro in mixed lymphocyte cultures in which lymphocyte function-associated antigen-1/intercellular adhesion molecule-1 or CD28/B7 interactions were blocked. Experiments using IL-4- or IFN-[Gamma]-deficient mice suggested a critical contribution of IFN-[Gamma] to the V[Alpha]14 NKT cell-mediated allograft acceptance in vivo. These results indicate a critical contribution of V[Alpha]14 NKT cells to the induction of allograft tolerance and provide a useful model to investigate the regulatory role of V[Alpha]14 NKT cells in various immune responses.