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HLA-G is a nonclassical MHC class I molecule and its physiological expression restricted to placental extravillous trophoblasts contributes to maternal tolerance to the semiallogeneic fetus. Aberrant expression of HLA-G in human organ grafts has been proposed to contribute to graft acceptance.We studied HLA-G expression in liver tissue and serum of adult liver transplant recipients before, early, and late after transplantation in relation to liver function and operational tolerance.Cirrhotic explant livers showed robust HLA-G expression on hepatocytes, whereas the majority of noncirrhotic livers and graft biopsies taken before or after liver transplantation (LTX) showed no, or weak, HLA-G expression. The HLA-G expression was induced on hepatocytes in vitro by TGF-β, but not by other relevant cytokines. Serum levels of the HLA-G isoforms 1 + 5 gradually declined after LTX. Early after LTX, serum HLA-G levels were higher in patients with acute rejection episodes than nonrejectors. Late after LTX, serum HLA-G levels did not differ between operationally tolerant patients and patients on regular immunosuppressive therapy.Our data do not support a graft-protective role for HLA-G after LTX, but show that end-stage liver diseases are associated with HLA-G expression on hepatocytes, which may determine a negative feedback to protect the liver against immunological damage.