Like allografts, vascularized xenografts are susceptible to a process of chronic rejection. We have used the hamster-to-rat aortic transplant model to study characteristics of this phenomenon and to determine whether it could be controlled or prevented by immunosuppressive therapy. Golden Syrian hamster aortas were transplanted into untreated Lewis rats, athymic rats, and Lewis rats receiving cyclosporin (10 mg/kg), leflunomide (5, 10 or 15 mg/kg), or 10 mg/kg of both drugs. Grafts were harvested on days 2, 7, 14, 28 and 56. Grafts and recipient spleens were analysed using computerized morphometry, immunohistochemistry and immunofluorescence. Blood was taken on various days for the measurement of anti-hamster antibodies (flow cytometry) and of the leflunomide metabolite A77 127. In untreated rats, by day 56, transplanted aortas developed a cell-free media with a mature neointimal lesion consisting of actin-positive cells, CD4 T cells, and macrophages. There were large increases in anti-hamster immunoglobulin M (IgM) and IgG, collections of proliferating cell nuclear antigen (PCNA)-positive cells in splenic germinal centres, and IgM, C3 and C5a deposition in aortas. In athymic recipients, the media architecture was preserved, and the changes in the neointima and in anti-hamster IgM and IgG were markedly abrogated, but not prevented. In Lewis rats receiving leflunomide, absence of circulating or deposited IgM did not prevent neointimal formation by day 14. Combination treatment was the most effective at preventing neointimal formation and humoral changes. Leflunomide monotherapy was the least effective. There were no changes in peak concentrations of the main metabolite of leflunomide over 8 weeks. The hamster-to-rat aortic transplant model is suitable for the study of xenograft vasculopathy, the histological and serological changes of which are predominantly T-cell dependent. Combination treatment with 10 mg/kg of cyclosporin and 10 mg/kg of leflunomide was most effective in preventing xenograft vasculopathy.