Passive immunoprophylaxis with hepatitis B immunoglobulin is used to reduce the risk of infection of grafts after liver transplantation and also to protect newborn children of hepatitis B virus-infected mothers. The use of hepatitis B immunoglobulin is associated with the emergence of variant viruses or escape mutants that have specific amino acid substitutions in immunodominant epitopes. Under these circumstances, high serum titres of the virus may be observed in the context of apparently protective levels of antibody to hepatitis B surface antigen. The potential impact of hepatitis B surface antigen variation on vaccination strategies remains a contentious issue. As the burden of hepatitis B virus is dramatically reduced by major vaccination programmes, a greater proportion of carriers will demonstrate hepatitis B surface antigen variation from wild-type. The degree of protection afforded by current vaccines from subsequent infection by variants of the virus is unknown. Concern is raised over the potential impact of hepatitis B surface antigen variation on hepatitis B virus polymerase inhibitor susceptibility, and the reduced sensitivity of current antigen assays for detection of hepatitis B surface antigen variants.