Increased hepatic expression of the Forkhead transcription factor FoxM1B in adult mice accelerates hepatocyte proliferation after partial hepatectomy, while in hepatocytes in intact liver the transgenic (Tg) protein is inactive and has no effect on proliferation. To investigate the influence of FoxM1B on liver tumor formation, we examined the effect of sustained enrichment of FoxM1B in the hepatocytes of mice treated with a diethylnitrosamine (DEN)/phenobarbital tumor induction protocol. Tg enrichment of FoxM1B in hepatocytes did not increase the proliferation rate in normal liver tissue even when the protein was localized to the nucleus. However, it did cause an increase in the proliferation rate and size of preneoplastic and early neoplastic lesions, although having no effects on the total numbers of these lesions. As tumors progressed to hepatocellular carcinomas, the additional Tg FoxM1B protein had no effect on cell proliferation, and there was no increase in tumor burden compared to wild-type animals. This suggests that the artificial enrichment of FoxM1B in the liver, which has been suggested as a gene therapy protocol for liver dysfunction with aging, may not be tumorigenic in that organ.