We investigated the efficacy of a preparation containing High Five (H5) insect cells infected with recombinant baculovirus encoding the murine interferon‐β gene (H5BVIFN‐β) against established primary tumors and occult lung metastases. Injection of live or lyophilized H5BVIFN‐β into established subcutaneous tumors of the highly metastatic murine UV‐2237m fibrosarcoma or K‐1735M2 melanoma in syngeneic mice eradicated both primary tumors and preexisting lung metastases. The therapeutic effects of H5BVIFN‐β were not observed in nude mice and were diminished in syngeneic mice depleted of CD4+ and CD8+ T cells. Immunohistochemical staining showed that tumors injected with H5BVIFN‐β were densely infiltrated by CD4+ and CD8+ T cells in mice with normal CD4/CD8 complement. These data demonstrate that, unlike most immunologic approaches in which prophylaxis can be achieved but eradication of established tumor is rare, lyophilized preparations of H5BVIFN‐β can serve as a novel immunotherapy against both primary tumors and their occult metastases. © 2002 Wiley‐Liss, Inc.