Accelerated coronary arteriosclerosis is one of the major complications in allogeneic cardiac transplantation, despite the significant improvement in immunosuppressive therapy. In this study we sought to clarify the cellular components in cardiac allograft arteriosclerotic lesions with monoclonal antibodies specific to either the muscle cell (HHF-35) or the macrophage (RAM-11). Four kinds of heterotopic transplantations were performed in the rabbit: (1) low cholesterol-fed (n = 5), (2) 1% cholesterol-fed (n = 5), (3) low cholesterol-fed and immunosuppressed (n = 6), and (4) 1% cholesterol-fed and immunosuppressed (n = 6). The donor hearts were removed after cardiac arrest in groups 1 and 2, and at 5 weeks after transplantation in groups 3 and 4. In groups 1 and 2 acute rejection was associated with slightly thickened intimal lesions composed of abundant infiltrating mononuclear cells and sparsely intermingled smooth-muscle cells. In group 3 the arterial intima were moderately thickened with the predominant proliferation of smooth-muscle cells. In group 4 coronary lumina were almost completely occupied with the intimal foam cells, which were derived mostly from macrophages and some from smooth-muscle cells. These data suggest that the proliferation of smooth-muscle cells might be a major factor contributing to arteriosclerosis in chronic cardiac rejection and that long-term exposure to hypercholesterolemia could induce the accumulation of smooth-muscle cells or macrophage-derived foam cells.