We have previously shown that inactivation of mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/ IGF2R) is a common early event in both human liver and breast carcinogenesis. The M6p/Igf2r is imprinted in mice while expression is biallelic in most humans. In this investigation the M6p/Igf2r gene is shown to also be imprinted in the liver of Fischer 344, Lewis and Brown Norway rats. In addition, we have identi®ed mutations in the expressed allele of the M6p/Igf2r in 40% of diethylnitrosamine-initiated rat liver tumors. These results provide further evidence that the M6P/IGF2R functions as a liver tumor suppressor gene. They also suggest that mice and rats would be more sensitive than humans to those hepatocarcinogens in which the M6p/ Igf2r is mechanistically involved in transformation since one rather than two alleles would need to be inactivated.