Tissue-type plasminogen activator (t-PA) is a widely used thrombolytic agent for treating acute myocardial infarction. Some previous studies suggest that t-PA benefits the heart independently of lysing coronary artery thrombi. The purpose of this study was to determine whether t-PA directly affects infarct size independently of lysing coronary thrombi, affects the no-reflow phenomenon, and exacerbates intramyocardial hemorrhage. We used a canine model of 2 hours of occlusion of the left anterior descending coronary artery followed by 4 hours of reperfusion. t-PA was administered 30 minutes after occlusion and was continued for 2 hours. Myocardial infarct size as a percentage of the risk zone was similar between saline (28 +/- 8%) and t-PA (35 +/- 9%) groups in a low-dose study and between saline (46 +/- 12%) and t-PA (44 +/- 12%) groups in a high-dose study. t-PA did not improve no-reflow. Intramyocardial hemoglobin level within the infarct was similar between saline (16 micrograms/mg) and high-dose t-PA (12 micrograms/mg) groups. The extent of hemorrhage assessed by intramyocardial hemoglobin correlated with infarct size. Histologic evaluation revealed that microscopic hemorrhage was confined to zones of contraction band necrosis. Neutrophil infiltration during early reperfusion was prominent. In conclusion, t-PA did not directly benefit the myocardium or no-reflow. Its effects in patients are likely due to its ability to lyse thrombi. t-PA did not cause infiltration of hemorrhage into noninfarcted tissue. Reperfusion accelerates the inflammatory response after myocardial infarction and results in early, intense neutrophil infiltration.