Recently we and others have shown that a combination therapy of cyclosporine (CsA) together with anti-B lymphocyte immunosuppressants such as cyclophosphamide (CY) or leflunomide (LF) resulted in a complete suppression of xenoantibody formation and long-term heart graft survival in a hamster to rat xenograft model. Here we show that three months after transplantation, functioning xenografts may develop signs of chronic vascular and/or interstitial lesions depending on the immunosuppressants used. A combination maintenance therapy of CsA (10 mg/kg/day) together with LF (10 mg/kg/day, continuously) resulted in a healthy interstitium and normal blood vessels without signs of chronic rejection. When LF was stopped after one month of therapy but CsA continued for the whole observation period, only some local interstitial fibrosis was noticed. In contrast, when CsA was stopped after one month but LF continued, a pronounced infiltration with mononuclear cells was found, together with clear intima proliferation and severe fibrosis. In conclusion, long-term surviving xenografts may offer a new model to study the pathogenesis and therapeutic approach of chronic transplant lesions. In this model, a maintenance therapy of CsA and LF was able to prevent all signs of chronic rejection.