A natural cytotoxic reactivity directed against syngeneic or allogeneic tumor cells was demonstrated in serum of BALB/c mice by an in vitro cytotoxicity test using rabbit serum as the source of complement. The reactivity, studied on syngeneic fibrosarcoma cells, was found to be minimal in mice less than 10 weeks old and to increase progressively with age. T-deprivation determined an increase of reactivity in young mice to levels reached spontaneously only by the serum of 40-week-old mice. The BALB/c serum also revealed natural anti-thymus antibodies. Non-identity between anti-tumor and anti-thymus antibodies was demonstrated by direct cytotoxicity and absorption tests. An inoculum of syngeneic fibrosarcoma cells increased the level of anti-tumor serum reactivity in both normal and T-deprived young mice. The natural anti-tumor cytotoxicity revelaed in vitro seemed to exert a specific in vivo protection as suggested by the indirect correlation found between the level of the natural anti-tumor reactivity and the grwoth of a transplanted fibrosarcoma.