Cyclosporine (CsA) is known to induce long-term survival of skin allografts, although the cellular mechanisms responsible for this effect are not well understood. To further define the effects of CsA-induced immunosuppression, we performed a morphological and immunohistological study of acute skin allograft rejection in the rat, comparing untreated and CsA-treated animals. Three significant differences were found between grafts in CsA-treated and untreated rats. First, CsA-allografts contained fewer MRC OX-8+ cytotoxic T cells than untreated allografts. Second, although the presence and numbers of infiltrating macrophages (W3/25+, W3/13- cells) was not influenced by CsA treatment, CsA treatment blocked expression of a macrophage membrane activation antigen, defined by the monoclonal antibody A1-3, which has previously been linked with development of macrophage procoagulant activity (PCA). Third, diminution in MRC OX-8+ lymphocytes and A1-3+ macrophages in CsA allografts was associated with an absence of the widespread thrombotic and necrotizing microvascular injury typical of acute rejection in untreated rats. We conclude that prolongation of skin allograft survival by CsA is related to its ability to prevent cell mediated injury to the endothelium of graft vessels, and possibly also to inhibition of macrophage PCA with consequent reduced thrombus formation.