“Escape” variants of hepatitis B virus (HBV) can cause infection despite previous immunization. These viruses show alterations of the immunogenic major hydrophilic loop of the HBV small surface protein (s-protein). We studied whether HBV “escape” variants were selected in patients with graft infection after liver transplantation for HBV-related diseases who received passive immunoprophylaxis with high-dose polyclonal hepatitis B hyperimmune globulin (HBIG). For that, pre- and posttransplantation sera of 34 patients were analyzed for the occurence of HBV S-gene variants. In addition, binding of in vitro–translated variant s-proteins to HBIG was studied. Variants with exchanges of amino acid (aa) 144 (s144) in HBV genotype A and 145 in genotype D (s145) were found to emerge, persist, and predominate during HBIG, and thus fulfilled criteria of “escape” variants selected. In addition to already-known variants sG145R/K/E, we could demonstrate that newly described variants sX144G and sG145A were antigenically altered and showed impaired recognition by polyclonal HBIG in vitro. Diminished recognition of variant s-proteins correlated with the failure of HBIG to prevent infection of the liver graft with antigenically altered variant HBV. Patients infected with “escape” variants s144 or s145 showed a worse clinical outcome compared with the other patients on high-dose, long-term HBIG prophylaxis (44% vs. 23% graft failure caused by HBV infection). Our results suggest that antigenically altered HBV variants s144 and s145 can be selected by HBIG and can influence clinical outcome after liver transplantation.