Estrogen displays potent immunoregulatory properties. In the present study we investigated the in vivo effect of estrogen on natural killer (NK) cell cytotoxic activity in several mouse strains. After castration, 17 beta-estradiol was administered in low or high doses. After 3-6 weeks of hormone administration an in vivo 51Cr-release assay with YAC-1 cells as target cells was performed. In all mouse strains, estradiol reduced NK cell cytotoxicity in a dose-dependent manner. However, some mouse strains displayed a high (> 50%) degree of estrogen-mediated suppression of NK cells (C3H/N, DBA/1, and NZB/W mice), whereas others displayed low (< 30%) susceptibility (C57BL/6 and MRLlpr/lpr mice). We also quantitated the frequency of Ig-producing spleen cells in mice receiving 17 beta-estradiol subcutaneously and/or antibodies to NK cells (anti-asialo GM1) intraperitoneally. Here, administration of estrogen for 31 weeks but not for 4 weeks significantly increased the frequency of IgG and IgM-producing cells. Repeated injections of anti-asialo GM1 for 4 weeks raised the frequency of IgG producing cells several-fold. We hypothesize that estrogen-mediated suppression of NK cells downregulates the inhibitory signals from these cells on B cells thus resulting in increased frequency of Ig-producing cells.