P8 80-100% incidence of multinodular hepatocellular carcinomas was observed in castrated male hamsters following synthetic estrogen treatment in the presence of 0.2-0.4% alpha-naphthoflavone (ANF) in the diet after 8.5-10 months. Induction of these liver tumors was detected as early as 3.5-4.0 months in low frequency. Of the synthetic estrogens studied, ethynylestradiol (CAS: 57-63-6) was a more potent inducer of these hepatic carcinomas than either diethylstilbestrol (CAS: 56-53-1) or hexestrol (CAS: 84-16-2). ANF, considered an inhibitor of P450-dependent multisubstrate monooxygenases, did not produce any liver tumors when administered alone for up to 12 months. Neither concomitant androgen nor progesterone (CAS: 57-83-0) treatment resulted in any hepatic carcinomas in animals maintained on ANF. Moreover, beta-naphthoflavone (CAS: 6051-87-2) treatment alone or in combination with these synthetic estrogens also resulted in no hepatic tumors. This new estrogen-induced liver tumor model could be useful to elucidate the casual relationship that exists between estrogenic hormones and hepatic tumors in humans.