The maintenance of skin allotolerance induced by perimetamorphic application of MHC-disparate skin to isogeneicXenopusis investigated. Removal of the perimetamorphically applied first-set graft after 4 weeks did not, in general, completely break allotolerance; however, many second-set semi-allogeneic grafts, applied up to 14 weeks after first-set removal, were no longer maintained in perfect condition. Skin allografts tolerated for up to 42 weeks continued to express donor histocompatibility antigens, as indicated by their survival times when transplanted back to the original donor or recipient strain. Treatment with human recombinant IL-2 (rIL-2), shown elsewhere to be an effective immunoregulatory lymphokine forXenopusin vivo, failed to cause long-term-tolerated lst-set allografts, or newlyapplied 2nd-set grafts, to be rejected. In contrast, cyclophosphamide (CyP) treatment led to acute (<4 weeks) destruction of both 1st- and 2nd-set allografts; breaking of tolerance was regularly seen when donor and host differed by two MHC haplotypes, but occurred infrequently in semiallogeneic combinations. The experiments suggest that skin-induced allotolerance is maintained by an immunosuppressive mechanism, that is CyP-sensitive but resistant to rIL-2 treatment.