Normal rabbit sera (NRS) obtained from noninbred animals were shown to contain antibody to YAC-1, a mouse lymphoma, in a complement-dependent 51Cr release assay. A positive correlation was found between the sensitivity to lysis by NRS antibody and the susceptibility to lysis by mouse natural killer (NK) cells when 7 mouse tumors and 1 guinea pig hepatoma were tested in both assay systems. This correlation was further established with a quantitative absorption assay in which NRS was absorbed with various mouse tumors and subsequently tested for cytotoxicity against YAC-1, the most NRS- and NK-sensitive tumor. A striking positive correlation appeared between the capacity to absorb the NRS anti-YAC-1 activity and the NK sensitivity of various mouse tumors to CBA spleen cells. Thymocytes from strain A/Sn mice less than 2 weeks old absorbed a substantial amount of the NRS anti-YAC-1 activity; these cells were also sensitive to mouse NK cytolysis, whereas thymocytes from older mice lacked both properties. These natural rabbit antibodies could not "arm" peripheral blood lymphocytes in the rabbit because 1) the peripheral blood lymphocytes from these animals used as serum donors showed only low cytotoxic activity in an NK assay against NK-sensitive mouse tumors, and 2) no positive correlation appeared between the levels of cytolytic activity and the levels of natural serum antibodies observed in the rabbits. The present data suggest that natural antibodies in NRS showed the same specificity pattern for mouse tumors displayed by mouse NK cells.