We have studied the expression of insulin-like growth factor II (IGF-II) during hepatocarcinogenesis in four independent transgenic mouse lines. In all four lines liver-directed transgene expression induces a stepwise and relatively synchronized tumorigenesis. IGF-II reexpression occurs in all four lines irrespective of the mechanism of tumor induction. Reexpression is chronologically associated with late progression steps toward hepatocellular carcinoma and correlated with the respective tumor progression rate in each line. IGF-II activation is focal and topographically associated with high replicative activity. IGF-II mRNAs in hepatocellular carcinomas show similarities to the expression pattern in fetal liver, and a M(r) 15,000 IGF-II polypeptide accumulates intracellularly in distinct cytoplasmic preferentially perinuclear compartments. These data indicate that IGF-II reexpression is a marker for progression to hepatocellular carcinoma and may contribute to hepatocarcinogenesis via an autocrine mechanism.