The effect of rapamycin (RPM) on the extent of arterial intimal thickening was determined in rat recipients of orthotopic femoral artery allografts or in rats that had undergone balloon catheter injury to carotid arteries. In untreated rats, neointima comprised approximately 50% of the arterial wall area in both models. Although treatment of allograft recipients for 40 days with 1.5 mg/kg/day RPM was ineffective, a dose of 6 mg/kg/day (days 0-7) followed by 3 mg/kg/day (days 8-39) reduced intimal thickening by 98% (P < 0.0001). The higher RPM dose reduced T cell and macrophage infiltration significantly and decreased the expression of IL-2 receptor, class II Ag, and mRNAs for growth factors and cytokines. Treatment with 1.5 mg/kg/day RPM (days 0-13) after balloon-catheter injury reduced intimal thickening by 45% (P = 0.0254) and substantially decreased macrophage infiltration and expression of class II Ag in the adventitia. Within the neointima, however, mRNAs for platelet-derived growth factor-alpha, basic fibroblast growth factor, and transforming growth factor-beta were still expressed. In summary, we have shown that RPM inhibits not only the vascular response to injury caused by allograft rejection, but also the response to balloon catheter injury. This new information is important to our understanding of: (1) the fundamental processes responsible for intimal thickening regardless of the cause of vascular injury, (2) mechanisms of action of RPM that explain its effects on the response to very different types of vascular injury, and (3) the potentially diverse therapeutic applications of drugs, like RPM, that inhibit the actions of both immune and nonimmune cytokines and growth factors.