The response of spleen and lymph node cells from tumor-bearing animals to a variety of mitogens was measured. It was found that progressive tumor growth diminished the reactivity of spleen cells to the mitogen phytohemagglutinin. Lymph node cells from the same animal were not consistently so affected. The reactivity of spleen cells from tumor-bearing donors to concanavalin A was somewhat depressed, while stimulation by bone marrow-derived lymphocyte mitogens such as endotoxin and pokeweed mitogen was in some cases enhanced. Theta antigen expression in tumor bearer spleens was found to decline steadily after 7 days of tumor growth. Cytological analysis revealed that the normal structure of the spleens of tumor animals was infiltrated by myeloid elements. The changes described occurred regardless of whether the tumors were chemically or virally induced. Excision of tumors after long periods of growth resulted in prompt return of splenic phytohemagglutinin sensitivity. The data suggests that loss or incapacitation of parts of the normal thymus-derived lymphocyte components may occur in the spleens of animals with progressive neoplastic growth.