We have related experimentally induced post-cardiac transplant coronary arteriopathy to increased elastolytic activity, IL-1 ␤ , fibronectin-mediated inflammatory and smooth muscle cell (SMC) migration, and SMC proliferation. Since our in vitro studies show that a serine elastase releases SMC mitogens and facilitates IL-1 ␤ induction of fibronectin, we hypothesized that administration in vivo of the specific serine elastase inhibitor, elafin, would decrease the post-cardiac transplant coronary arteriopathy. Cholesterol-fed rabbits underwent a heterotopic cardiac transplant without immunosuppression and received elafin (1.79 mg/kg per d continuous infusion after a 9 mg bolus, n ϭ 6) or vehicle ( n ϭ 6). 1 wk later, hearts were harvested for morphometric, immunohistochemical, and biochemical analyses. A Ͼ 70% decrease in the total number of coronary arteries with intimal thickening in elafin-treated compared to control donor hearts ( P Ͻ 0.002) was associated with reduced vascular elastolytic activity judged by fewer breaks in the internal elastic lamina ( P Ͻ 0.03), less accumulation of immunoreactive fibronectin ( P Ͻ 0.02), and reduced cell proliferation quantified by proliferating cell nuclear antigen ( P Ͻ 0.0001). Despite myocardial lymphocytic infiltration, wet weight of elafin-treated donor hearts was reduced by 50% compared to untreated controls ( P Ͻ 0.002) and associated with relative preservation of myocyte integrity, instead of extensive myocardial necrosis ( P Ͻ 0.004). This protective effect correlated with decreased myocardial elastolytic activity ( P Ͻ 0.0001) and inflammatory cell proliferation ( P Ͻ 0.0001) and with an elafin-inhibitable elastase in lymphocytes. Serine elastase activity thus appears an important therapeutic target for post-cardiac transplant coronary arteriopathy and myocardial necrosis induced by rejection. ( J. Clin. Invest. 1996. 97:2452-2468.)