Hepatic hyperplastic nodules (HHNs) in rats were studied as an experimental prototype of oral contraceptive-related hepatic tumors. We have found cytoplasmic estrogen receptors in HHNs produced by acetylaminofluorene (AAF) (four cycles of 0.02% in diet). Rats with AAF-induced HHNs were randomized into four groups: (i) AAF-treated control; (ii) estrogen alone (estradiol-17β); (iii) tamoxifen alone, and (iv) estrogen + tamoxifen. After 8 months of treatment with estrogen (estradiol-17β) in combination with tamoxifen, there was regression of nodular involvement and no evidence of malignant transformation. Decreased nodular proliferation also occurred after 2 and 4 months treatment with estradiol-17β and after 8 months of tamoxifen administration. The incidence of hepatocellular carcinoma after 8 months of treatment was significantly less after treatment with estrogen (40%) or tamoxifen (42.9%) when compared to AAF-treated controls (87.5%). The number of -γ-glutamyitranspeptidase-positive foci were reduced in all treatment groups after 2,4, and 8 months of treatment; these changes were most pronounced in the estrogen-treated group and did not directly correlate with the per cent inhibition of malignant transformation. Our results suggest that the malignant transformation of estrogen receptor-positive HHNs is hormone dependent.