We examined interferon (IFN)-alpha therapy in animal models from the immunological aspects. Long after the cessation of successful IFN administration there found a strong tumor neutralizing activity of spleen T cells in the curing mice. However, this activity was not detectable right after the cessation of IFN administration. Instead, in this early stage, a strong tumor neutralizing activity was found in the lymph nodes of IFN-administered mice. This does not necessarily indicate that the primary modifying target of IFN was T cells since IFN is not capable of directly activating T cells. Further experimentation showed that IFN administration resulted in the very fast production of antitumor monocytes in peripheral blood. Again, this may not be a primary modifying target of IFN since IFN is a very poor activator of monocytes and macrophages and sometimes a very strong nullifier of activation of these cells. Based on these results and those reported in the literatures, it was discussed what would be a real modifying target of IFN in association with the therapeutic effect.