The use of El-deleted recombinant adenoviruses in gene therapy has consistently been associated with transient gene expression and inflammation due to immune-based destruction of the Infected cells. We have used murine models of adenovirus-medlated gene transfer to liver to investigate these immunologic mechanisms. Adoptive transfer experiments, as well as studies involving genetic knockout mice, confirmed the original hypothesis that cell-mediated immunity induced by El-deleted adenovlrus destroyed transgene-expressing hepatocytes and defined MHC class I-restricted CD@ cytolytic lymphocytes as the primary immune effecters for hepatocyte destruction. Responses mediated by CD4+ cells per se were insufficient to mediate destruction of hepatocytes in vivo, despite the activation of virus-specific T helper cells of Thl subsets. A better understanding of the response of the host to in vivo gene therapy is important in evaluating its usefulness in humans.