A factor in the incidence of spontaneous neoplasms in mice is the endogenous level of natural cell-mediated cytotoxicity. These immunosurveillant or host defense mechanisms are probably under the control of multiple gene products including interferons. We studied natural killer (NK) cytotoxicity using peripheral blood mononuclear cells from 59 normal individuals with either a high (17) or low (42) familial incidence of breast cancer. The K562 cell line was used as target in 51Cr release assays. Three effector: target ratios (6.2:1, 25:1, and 50:1) were studied in quadruplicate using 3, 4 and 5-h incubations. Significantly lower natural killer activity (p less than 0.002) was detected in normal individuals with high familial incidences of breast cancer compared to individuals with low incidences in each of the three separate assays (50:1). The same conclusion was reached whether the data were expressed in terms of lytic units per 10(7) blood mononuclear cells or as % specific 51Cr released. Thus, a relationship was observed between the occurrence of breast cancer in closely related family members and low natural cell-mediated cytotoxicity. This result suggests that defects in NK activity may play a role in the initiation of human breast tumors. However, prospective studies will be necessary to establish whether low NK cell activity is a risk factor for breast cancer.