In a group of 39 patients who received fibrinolytic therapy for acute myocardial infarction, serum crosslinked fibrin degradation products (XLDP) were quantitated by an enzymelinked immunosorbent assay (ELISA) using an antibody reactive with a site near the yy crosslink of fibrin, and characterized by a gel electrophoretic method to distinguish fibrinogen degradation products (FDP) from XLDP. After coronary artery reperfusion, 63 of 81 (69%) serum samples showed XLDP by gel analysis, whereas the incidence of positive samples before reperfusion, 53 of 144 (37%), was significantly less (p < .0001). The first appearance of serum XLDP by gel analysis was most often in the 15 min interval immediately before or after angiographic documentation of reperfusion, and the elapsed treatment time required to produce a positive test was shorter with more intensive treatment regimens. However, the appearance of serum XLDP was not a specific indicator of reperfusion in individual patients, since one or more serum samples was positive in five of eight patients who did not show reperfusion as well as in 27 of 29 patients who did show reperfusion. Furthermore, the concentration of serum XLDP as measured by ELISA showed no significant difference in samples from patients who did or did not have reperfusion or between samples taken before or after reperfusion. There was a close temporal correlation between the first appearance of serum XLDP (gel analysis) and the initial decrease in plasma fibrinogen (systemic lytic state), and the degree of elevation of serum XLDP (ELISA) was also correlated with the intensity of the systemic lytic state. In addition, electrophoretic analysis of pretreatment plasma samples demonstrated crosslinked fibrin polymers that disappeared during fibrinolytic therapy coincident with the appearance of serum XLDP and in parallel with fibrinogen conversion to degradation products (fragments X, Y, and D). Two patients without a lytic state showed no change in plasma fibrin polymers during therapy, and XLDP were not present in serum despite coronary reperfusion in one patient. Thus the results indicate that XLDP appearing in the blood during fibrinolytic therapy for acute myocardial infarction are not predictive of successful fibrinolytic therapy, but rather may reflect degradation of circulating fibrin polymers associated with the fibrinogenolysis of the systemic lytic state.