The objective of this study was to determine the clinical significance of fibrinogenolysis in patients with isolated closed head injury. We correlated indices of fibrinolytic activity, fibrinogen degradation products (FgDP), and fibrin degradation products (FbDP) with outcome in order to accomplish this. This study consisted of 40 patients with isolated closed head trauma in whom blood sampling could be initiated within 3 h after injury. Patients were divided into two groups according to Glasgow Outcome Scale status at 3 months after injury, characterized as good recovery or moderate disability (group 1, n = 21); and severe disability, vegetative, or death (group 2, n = 19). The plasma fibrinogen concentration correlated with the Glasgow Coma Scale score on admission (r2 = 0.201, p < 0.01), and plasma fibrinogen concentrations in group 2 were lower than in group 1 (p < 0.05). Plasma concentrations of fibrin/fibrinogen degradation products (FDP) and plasmin-alpha2-plasmin inhibitor complex (PIC), molecular markers of activation of fibrinolysis, were higher in group 2 than in group 1 (p < 0.001), and both FgDP and FbDP concentrations in group 2 also were higher than in group 1 (p < 0.001). Both the FgDP and FbDP concentrations correlated with the PIC concentration. Moreover, the plasma FgDP concentrations correlated inversely with alpha2-plasmin inhibitor activity, a potent inhibitor of the fibrinolytic sysytem, as did the FbDP concentration. This study reveals that both fibrinolysis and fibrinogenolysis are involved in the coagulopathy that develops during the acute phase of head injury and correlate with fibrinolytic activity. Decreased activity of alpha2-plasmin inhibitor may contribute to fibrinogenolysis.