Hepatocellular injury during hepatitis B virus (HBV) infection has been postulated to result from a human leukocyte antigen (HLA)-restricted T-lymphocyte host immune response against HBV antigens. Although HLA expression is enhanced in the presence of hepatic inflammation, whether HBV itself can induce HLA expression on infected hepatocytes is unknown. In this study, we demonstrate the induction of HLA-DR expression on human hepatoma cell lines transfected with HBV DNA sequences. The HBV X gene alone was capable of inducing HLA-DR expression. This induction correlated with elevated HLA-DR RNA, and this resulted directly from transcriptional trans-activation of the HLA-DR gene by the HBV X protein. These studies suggest that the HBV X protein can regulate the expression of HLA-DR and thus raise the possibility of participation by the X gene in the immunopathogenesis of HBV infection.