Phage phiC31 integrase is a site-specific recombinase that mediates efficient integration of circular extrachromosomal DNA into the host genome. Here, the integrase system was used to transfer the fumarylacetoacetate hydrolase (FAH) gene into the liver of mice affected with hereditary tyrosinemia type 1. Approximately 3.6% of transfected hepatocytes experienced an integration event. The absolute frequency of integration was 1/1374. A higher proportion of integrase-transfected FAH+ hepatocytes displayed abnormal morphology (bizarre nuclei, enlarged cells) on day 25 after gene transfer, compared to cells not receiving integrase. The increased frequency of these abnormal cells correlated with the amount of integrase plasmid administered, suggesting some form of integrase toxicity in Fah-/- livers. The abnormal hepatocyte appearance was transient and livers analyzed after longer selection (90 days) showed 60% repopulation with only normal healthy FAH+ hepatocytes. A total of seven different integration sites (accounting for >90% of integration) were identified. Serial transplantation of integrase-corrected hepatocytes to Fah-/- recipients was successful, suggesting long-term viability of corrected cells and persistent gene expression through many rounds of cell division. The stability of transgene expression, relatively high integration frequency, and significant site specificity that characterize the phiC31 integration system suggest that it may have utility in many gene therapy settings.