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Three models of specific unresponsiveness to skin allografts have been developed in adult mice immunosuppressed with antilymphocyte serum (ALS). In the first model, mice are thymectomized, treated with ALS, and injected with 300 ± 106 hybrid lymphoid cells. These mice accept donor skin grafts permanently and are lymphoid cell chimeras. In the second model, nonthymectomized, ALS-treated mice are injected with 25 ± 106 nonhybrid, homozygous allogeneic bone marrow cells. Although survival of skin allografts is significantly prolonged in these mice, it is not permanent and the recipients are not chimeras. In the third model, recipients are thymectomized before ALS treatment and injection of 25 ± 106 allogeneic marrow cells. A majority of these mice maintain donor skin grafts for over 100 days and 40% survive permanently, although they are not chimeras. The effect of Cytoxan on induction of unresponsiveness was studied in these models. Cytoxan was given before cellular antigen and skin graft survival was compared in Cytoxan-treated mice versus mice given no Cytoxan. Cytoxan reduced the enhancing effect of marrow in nonthymectomized, ALS-treated mice. In contrast, Cytoxan had no effect on the induction of unresponsiveness' in either thymectomized model. It is possible that suppressor cells, known to be sensitive to Cytoxan, may be required for the induction and/or maintenance of unresponsiveness to skin allografts in nonthymectomized, but not in thymectomized mice.