The inflammatory response after prolonged ischemia and subsequent reperfusion leads to increased risk of primary organ dysfunction after cardiac transplantation. It has been demonstrated that the fibrin-derived peptide Bbeta(15-42) (also called FX06) reduces infarct size in coronary artery occlusion/reperfusion models by inhibition of leukocyte migration. Further, Bbeta(15-42) preserves endothelial barrier function. The purpose of this study was to investigate whether Bbeta(15-42) has a protective effect in cardiac allografts exposed to prolonged global ischemia and subsequent in vivo reperfusion. Hearts of male Lewis rats were flushed and stored in cold Bretschneider preservation solution for 4 or 8 hr. Bbeta(15-42) was administered before being transplanted into syngeneic recipients. Serum samples were collected for troponin-T measurements. Hemodynamic performance was evaluated after a reperfusion period of 24 hr. Morphologic quantification of myocardial necrosis was performed in hearts exposed to 24 hr or 10 days of reperfusion. Allografts from Bbeta(15-42) treated animals showed less myocardial necrosis (2.5% +/- 2.5% vs. 18.4% +/- 9.2%, P=0.0019) and decreased values of cardiac troponin-T (1.1 +/- 0.6 ng/mL vs. 2.7+/-2.3 ng/mL, P=0.0045), reduced number of infiltrating leukocytes (7.2 +/- 13.6 vs. 49.2 +/- 34.9 per high powerfield, P=0.0045), and superior cardiac output (78.1 +/- 1.8 mL/min vs. 21.7 +/- 4 mL/min, P = 0.0034). Hearts exposed to 0 and 4 hr of ischemia showed no severe signs of myocardial damage. Bbeta(15-42) ameliorates the ischemia-reperfusion injury in transplanted hearts during extended cold ischemia by reduction of infiltrating leukocytes. This experimental protocol provides evidence that Bbeta(15-42) may play a useful role in organ preservation, but clinical evaluation is warranted.