Histone H1 and high-mobility group box 1 (HMGB1) proteins are known to initiate an immune reaction, and the corresponding antibodies (Abs) possess immunosuppressive activity. In the present study, we aimed to evaluate the immunological role of antinuclear Abs in experimental and clinical liver transplantation. In a rat tolerogenic orthotopic liver transplantation (OLT) model, antihistone H1 and HMGB1 titers were induced during the rejection and tolerance induction phases, respectively. Those Ab responses also were confirmed in a drug-induced tolerance model (acute rejection model + cyclosporin A [0 to 14 days after OLT]). We also found a similar tendency in our clinical drug-free patient (who experienced complete cessation of any immunosuppressive treatments) and that antinuclear Abs induced in the serum after cessation of immunosuppressants play a part of immune privilege in this patient. These results suggest that antinuclear Abs are important factors for overcoming rejection and the subsequent tolerance induction in liver transplantation.