BACKGROUND: Despite the risks associated with transfusion, the medical community continues to view blood as a safe and abundant product. In this article, we provide an effective strategy to accomplish orthotopic liver transplantation without transfusion. STUDY DESIGN: From June 1999 through July 2004, 27 liver transplantations were performed in Jehovah's Witness patients at the USC-University Hospital (24 adults, 3 children). Nineteen of these were living donor (LD) and eight were deceased donor (DD) liver transplants. Preoperative blood augmentation with erythropoietin and iron was achieved. At induction, all LD and six of eight DD recipients underwent acute normovolemic hemodilution (ANH), and the operation was conducted under conditions of moderate anemia. Cell scavenging techniques were used. Acute normovolemic hemodilution and salvaged blood were returned as needed during bleeding or on completion of transplantation. RESULTS: The preoperative liver disease severity score was higher in the deceased donor group. We had 100% graft and patient survivals in the LD group, and 75% in the DD recipients. Two DD recipients died. The remaining are all alive and well, with a mean followup of 965 days (range 266 to 1,979 days) in the LD group and 624 days (range 119 to 1,132 days) in the DD group. CONCLUSIONS: Preoperative blood augmentation and acute normovolemic hemodilution provide a safe cushion against operative blood loss. Elective living donor liver transplantation allows full implementation of a transfusion-free strategy in the setting of early hepatic failure, portal hypertension, and anemia. This feat is an important step toward global standardization of transfusion-free surgical practice and an important response to widespread blood shortages and transfusion risks.