Spleen cells from C57BL/6J mice bearing Ehrlich carcinoma growing as a solid tumor show progressive unresponsiveness to concanavalin A (Con A) and lipopolysaccharide (LPS) mitogens. This is accompanied by striking spleen enlargement with marked hematopoietic activity. Lymphoproliferative assays of normal spleen cells in co-culture with tumor-bearing spleen cells (TBSC) show that: (a) TBSC contain non-specific suppressor cells able to abrogate both Con A and LPS responses, or mixed lymphocyte reaction, of normal spleen cells and (b) suppression by TBSC is MHC-unrestricted, non-prostaglandin-mediated and greatly enhanced by Con A supernatants. Suppressor cells associated with TBSC are large, low-density cells without markers of mature B or T lymphocytes or of the mononuclear phagocyte system. Most appear to be asialo-GM1-negative, as suppression was only partially inhibited by treatment with anti-asialo-GM1 and complement. Since NK activity is lacking in TBSC, our data strongly suggest that these "null" suppressor cells are related to the natural suppressor (NS) cells found described in normal bone-marrow and neonatal spleens, or induced in adult spleens by total lymphoid irradiation, graft-vs.-host disease, or cyclophosphamide treatment.