Rat aortic allografts from the DA (RT1a) to the WF (RT1v) strain but not syngeneic DA-to-DA control grafts develop arteriosclerotic changes in the vascular wall that are virtually identical to human allografts during chronic rejection. A more prominent medial cell destruction in the rat aorta, leading ultimately to complete medial necrosis, is the major difference between rat and human allografts. If the adventitia of syngeneic grafts is exposed to starch before transplantation, these grafts also develop an inflammatory reaction in the adventitia and an extensive intimal thickening at the site of the granulomas, but the medial smooth muscle cells are preserved. In both types of transplants with an intact endothelium as determined by light microscopy, adventitial inflammatory cell proliferation was accompanied by smooth muscle cell replication in the media and thickening of the intima. We therefore propose that an adventitial proliferative response is a prerequisite for intimal thickening to occur. In the allograft but not in starch-exposed syngeneic grafts there was also a notable lymphoid activation in the adventitia, which was accompanied by medial necrosis. We suggest that the medial necrosis in the allograft is linked to a toxic effect of activated lymphoid cells on medial myocytes and is not a prerequisite for intimal proliferation. Instead, intimal proliferation and medial necrosis in the allograft seem to be independently regulated.