Natural antibodies reacting in a test of complement-dependent cytotoxicity with untreated murine lymphosarcoma cells of thymic origin were found in murine sera. Normal thymus cells were unaffected and unable to absorb the serum activity. The natural antibodies were lgM-like and stable at 56° C. They were not uniformly distributed in the studied strains, and high (C3H/He and C3Hf), intermediate (AKR and CBA/J), and low level strains (BALB/c, DBA/2, C57BL, and C57BL/6J) were found. Hybrids between a high (C3Hf) and a low level strain (C57BL) had the same response as the parental C3Hf mice. An inverse relationship was demonstrated between cytotoxicity of, and susceptibility to, serum of lymphoma cells in a given strain, which suggested that an immunologic modulation was at work. Embryonic cells absorbed the cytotoxic activity of the normal serum.