Immunomodulators are effective in controlling hematologic malignancy by initiating or reactivating host antitumor immunity to otherwise poorly immunogenic and immune suppressive cancers. We aimed to boost antitumor immunity in B-cell lymphoma by developing a tumor cell vaccine incorporating (a-galactosylceramide (a-GalCer) that targets the immune adjuvant properties of NKT cells. In the E?-myc transgenic mouse model, single therapeutic vaccination of irradiated, (a-GalCer-loaded autologous tumor cells was sufficient to significantly inhibit growth of established tumors and prolong survival. Vaccine-induced antilymphoma immunity required NKT cells, NK cells, and CD8 T cells, and early IL-12-dependent production of IFN-?. CD4 T cells, gamma/delta T cells, and IL-18 were not critical. Vaccine treatment induced a large systemic spike of IFN-(? and transient peripheral expansion of both NKT cells and NK cells, the major sources of IFN-?. Furthermore, this vaccine approach was assessed in several other hematopoietic tumor models and was also therapeutically effective against AMLETO9a acute myeloid leukemia. Replacing (a-GalCer with ?-mannosylceramide resulted in prolonged protection against E?-myc lymphoma. Overall, our results demonstrate a potent immune adjuvant effect of NKT cell ligands in therapeutic anticancer vaccination against oncogenedriven lymphomas, and this work supports clinical investigation of NKT cell-based immunotherapy in patients with hematologic malignancies.