BACKGROUND & AIMS:: Mutations in components of the Wnt signaling pathway, including beta-catenin and AXIN1, are found in more than 50% of human hepatocellular carcinomas (HCCs). Disruption of Axin1causes embryonic lethality in mice. We generated mice with conditional disruption of Axin1to study its function specifically in adult liver. METHODS:: Mice with a LoxP-flanked allele of Axin1were generated by homologous recombination. Mice homozygous for the Axin1fl/fl allele were crossed with AhCre mice; in offspring, Axin1was disrupted in liver following injection of -naphthoflavone ( Axin1fl/fl / Cre mice). Liver tissues were collected and analyzed by quantitative real-time PCR and immunoprecipitation, histologic, and immunoblot assays. RESULTS:: Deletion of Axin1 from livers of adult mice resulted in an acute and persistent increase in hepatocyte cell volume, proliferation, and transcription of genes that induce the G2-M transition in the cell cycle and cytokinesis. A subset of Wnt target genes were activated, including Axin2, c-Myc, and cyclin D1. However, loss of Axin1 did not increase nuclear levels of beta-catenin or cause changes in liver zonation that have been associated with loss of the adenomatous polyposis coli (APC) or constitutive activation of beta-catenin. After 1 year, 5 of 9 Axin1fl/fl/Cre mice developed liver tumors with histologic features of HCC. CONCLUSION:: Hepatocytes from adult mice with conditional disruption of Axin1 in liver have a transcriptional profile that differs from that associated with loss of APC or constitutive activation of beta-catenin. It might be similar to a proliferation profile observed in a subset of human HCCs with mutations in AXIN1. Axin1fl/fl mice could be a useful model of AXIN1-associated tumorigenesis and HCC.