Recombinant retroviral vectors are an attractive means of transferring genes into the liver because they integrate into the host cell genome and result in permanent gene expression. However, efficient in vivo gene transfer is limited by the requirement of active cell division for integration. Traditional approaches to induce liver proliferation have the disadvantage of inducing hepatocellular injury by delivery of toxins or by surgical partial hepatectomy. As a nontraumatic alternative, we show that exogenous hepatocyte growth factor (HGF) is a powerful and safe mitogen for the mature intact murine liver when delivered continuously into the portal vein. A 5-day infusion of human HGF (5 mg/kg/d) resulted in > 140% increase in relative liver mass, which returned to normal in 4 to 5 weeks. This clearly shows that an exogenous growth factor can induce robust liver proliferation in vivo. In addition, we show that the HGF-induced proliferation was independent of interleukin-6, an essential cytokine involved in liver regeneration after partial hepatectomy. When recombinant retroviral vectors were infused in combination with HGF, 30% of hepatocytes were stably transduced with no indication of hepatic injury or histopathology. These results show the ability to obtain a clinically relevant transduction efficiency with retroviral vectors in vivo without the prior induction of liver injury. The level of hepatic gene transfer achieved has the potential to be curative for a large number of genetic liver diseases.