Administration of interferons (IFN) via the intranasal route recently has been shown to exert an antitumor activity against a variety of tumors in mice, including B16 melanoma inoculated intravenously. This study confirms the antitumor activity of orally administered IFN-alpha against B16 melanoma challenge using another route of tumor inoculation, the intraperitoneal route. It further demonstrates that orally administered IFN-alpha can synergistically interact with intraperitoneally administered IFN-gamma but not with intraperitoneally administered IFN-alpha. The results support the interpretation that the oral route may provide an effective alternative or supplement to current methods of IFN administration for the control of malignancies.