Livers but not hearts are accepted spontaneously without immunosuppression when transplanted from B10 (KbAbEbDb) to C3H (KkAkEkDk) mice. Both organs however, undergo accelerated rejection in C3H recipients presensitized with B10 skin grafts. In this study, we have investigated further the role of functional cell-surface major histocompatibility complex (MHC class I or class II molecules in allosensitization. Skin from transgenic MHC class I (b2mmlUncbcr; AbEb) or class II (C2DTM, KbDb) gene 'knockout' mice was grafted onto naive recipients 2-3 weeks prior to whole organ transplantation. When C3H hosts were presensitized with skin from C2DTM (class II deficient) mice, they promptly rejected (within 4 days) subsequently transplanted B10 liver or heart allografts. In contrast, presensitization with skin from b2m (beta 2-m mutant; class I deficient) mice did not significantly affect the survival of either organ graft. Maximal sensitization was established by day 14 after skin grafting and persisted for at least 12 weeks. Splenocytes obtained from C3H mice sensitized with skin from B10, B6 (KbAbEbDb), or C2DTM but not from b2m mice exhibited an H-2b-specific cytolytic response when tested in cell-mediated lymphocytotoxicity assays. Sera from C3H mice sensitized with B10 or b2m skin contained high titres of cytotoxic activity specifically against H-2b class I. Taken together, these observations suggest that in the strain combination studied, MHC class I rather than class II molecules play an important role in allosensitization. The results indicate the potential importance of avoiding transplantation of organs into recipients of secondary grafts from donors that share human leucocyte antigen (HLA) class I antigens with the first donor.