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A number of problems are described which must be surmounted for the clinical use of liver homotransplantation, based upon experience with 3 patients. The first patient died of hemorrhage during conclusion of the operation. The second and third patients lived for 22 and 7½ days, respectively, both ultimately dying from multiple pulmonary emboli. The operative requirements for successful liver transplantation appear to be subject to practical solution. Of the utmost importance is the procurement of a viable and relatively undamaged donor organ. This has been accomplished with the use of an extracorporeal circuit which perfuses and cools the liver immediately after death. In addition, the time interval between death of the donor and restoration of a hepatic blood supply in the transplanted site has been shortened by operating on the recipient patient in 2 stages. At the preliminary operation, all structures are skeletonized above and below the liver with facilitation of the recipient hepatectomy and multiple anastomoses which are performed at the second and definitive procedure. While the transplantation is being performed, the venous return from the splanchnic and inferior vena caval systems is temporarily occluded. It has been found necessary to decompress only the inferior vena cava during this time with an external bypass from the inferior to the superior vena caval systems. Changes in the coagulation mechanisms constitute a serious deterrent to success. During operation, a bleeding diathesis is regularly detectable by laboratory examination. Postoperatively, a state of hypercoagulability has developed, which probably contributed to the lethal complication of multiple pulmonary embolization in 2 patients. It is also possible that the use of the external bypass contributed to the formation of the emboli. After operation, hepatic functions were immediately deranged, probably as the result of injury incurred during the transplantation, with progressive improvement thereafter. Later, biochemical evidence of homograft rejection was not observed, and at autopsy in the last 2 patients there was surprisingly good gross and histologic preservation of graft structure. It is thought that the therapy with azathioprine, prednisone, and actinomycin C had forestalled the rejection process.