Male Sprague-Dawley rats were given a single intraperitoneal injection of diethylnitrosamine (DEN, 200 mg/kg body weight). Two weeks later the rats were divided into 4 groups; DEN-C group rats were given no further treatment; DEN-DES group rats were fed diethylstilbestrol (DES, 0.5 mg/day); DEN-TMX group rats were given tamoxifen (TMX, 1.0 mg/day) orally; DEN-DES TMX group rats were fed both DES and TMX for 8 months. Rats of the DEN-DES group developed grossly visible hepatic tumors. On the other hand, tumor development was significantly inhibited in rats of the DEN-DES TMX group. Total area of gamma-glutamyl transpeptidase-positive lesions and the mean area per lesion were significantly larger in rats of the DEN-DES group than those of the DEN-C, DEN-TMX or DEN-DES-TMX group. Estrogen receptor (ER) content of liver cytosol assayed by enzyme immunoassay (EIA) was significantly greater in rats of the DEN-DES group than in those of the DEN-C group and smaller in rats of the DEN-TMX and DEN-DES TMX group than in the DEN-C group. On the contrary, ER content of liver nuclei was significantly greater in rats of the DEN-TMX and DEN-DES TMX group than in those of the DEN-C or DEN-DES group. These results suggest that the promotive action of DES and the inhibitory action of TMX on DES-promoted hepatic tumorigenesis are, at least in part, mediated by ER in the rat.