Treatment of mice with 17 beta-estradiol leads to a selective inhibition of natural killer (NK) cell activity as measured by in vitro cytotoxicity against YAC-1 lymphoma and UV-2237 fibrosarcoma target cells. Activation of NK cells by polyinosinic-polycytidylic acid (poly I.C) and Corynebacterium parvum also was impaired in beta-estradiol-treated mice, whereas activation of tumoricidal macrophages was uncompromised. The beta-estradiol-induced suppression of NK cell activity was associated with a higher incidence of experimental and spontaneous pulmonary metastasis of the syngeneic UV-2237 fibrosarcoma and K-1735 and B16 melanoma tumors. Injection of poly I.C or C. parvum before i.v. tumor challenge markedly inhibited the development of lung tumor colonies in normal recipients, but it was less effective in beta-estradiol-treated mice. Adoptive transfer of normal spleen cells enhanced the NK cell activity and increased the resistance of beta-estradiol-treated mice against hematogenous tumor metastasis. Nude mice treated with beta-estradiol also exhibited a low level of NK cell activity and an enhanced susceptibility to metastasis of allogeneic tumor cells. The potential use of this in vivo model for studies of metastasis of human malignant neoplasms is discussed.