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The liver has long been recognized as having tolerogenic properties. We investigated whether recombinant adenoassociated virus (rAAV)–mediated expression of donor major histocompatibility complex in recipient livers could induce tolerance to donor-strain grafts.Naive B10.BR (H-2k) or B10.BR recipients primed with a H-2Kb–expressing (Kb+) skin graft were injected with rAAV-expressing H-2Kb (rAAV-Kb) to induce Kb expression on hepatocytes 7 days before challenge with a Kb+ skin graft. Kb-specific responses were measured by interferon (IFN)-γ ELISpot and flow cytometric assessment of directly H-2Kb reactive cells. Fully allogeneic grafts from C57BL/6 (H-2b) donors were transplanted onto longstanding B10.BR recipients of Kb+ skin to test for linked epitope suppression.rAAV-Kb–treated B10.BR mice accepted Kb+ skin grafts with increased median survival time (MST) more than 169 days compared to uninoculated (MST=18.5 days) and rAAV-Kd–treated controls (MST=19 days). rAAV-Kb–treated B10.BR animals primed with Kb+ skin grafts also accepted secondary Kb+ skin grafts in the long term (MST>100 days) compared to accelerated rejection in primed, uninoculated mice (MST=12 days). Treatments did not induce liver pathology, assessed by serum alanine aminotransferase levels and histology. IFN-γ ELISpot analysis of splenocytes from rAAV-Kb–treated mice indicated reduced responses to donor Kb+ antigen, but protection was not extended to fully allogeneic C57BL/6 skin or heart grafts, even in recipients that had accepted Kb+ skin grafts in the long term.High-level expression of donor major histocompatibility complex in recipient livers promotes tolerance to skin allografts, even in animals primed to produce a memory response. This provides proof of concept for an approach using liver-targeted gene delivery for tolerance induction to donor antigen.