The determination of differences in hormonal regulation of tumor promotion-related response to 2,3,7,8-tetrachlorodibenzop-dioxin (TCDD) between males and females may identify factors contributing to the female-specific hepatocarcinogenicity of TCDD in rats. In the current study, diethylnitrosamine-initiated male Sprague-Dawley rats were exposed to TCDD or corn oil vehicle in the presence and absence of 17beta-estradiol (E2), and cell proliferation and development of preneoplastic altered hepatic foci (AHF) were determined. After 30 weeks of exposure, gamma-glutamyltranspeptidase (GGT)-positive AHF and the number of placental glutathione-s-transferase (PGST)-positive AHF were significantly higher in TCDD-treated rats than in control rats. Both the number and volume fraction of GGT-positive AHF were significantly lower in rats cotreated with E2 regardless of TCDD exposure compared with corresponding non-E2-treated groups and were unaffected by TCDD. In contrast, the number of PGST-positive AHF was significantly higher in E2-treated rats in the absence of TCDD treatment. In addition, whereas E2 had no effect on the volume fraction of PGST-positive foci, the levels in rats cotreated with both E2 and TCDD were significantly higher than in controls. No differences were observed in cell proliferation between TCDD-treated and control rats, although cell proliferation was lower in rats exposed to E2 compared with placebo controls. The weaker potency of tumor promotion and lack of induction of cell replication and DNA damage in male rats likely explain the female-specific hepatocarcinogenicity of TCDD in chronic bioassays.