Six patients with disseminated intravascular coagulation (DIC) in association with acute promyelocytic leukemia (APL) were studied with sensitive radioimmunoassays that are able to quantitate the extent of thrombin generation within the human circulation. The levels of prothrombin activation fragment, F1 + 2, and thrombin-antithrombin complex (TAT) were obtained at clinical presentation and were then followed serially in several patients during induction chemotherapy. The antileukemic therapy often resulted in a rise in the plasma levels of these molecular species. Simultaneous measurements of fibrinopeptide A (FPA) were also obtained, and the concentrations of this polypeptide were correlated with the levels of F1 + 2 and TAT in patients who were not receiving heparin. Nine individuals with other morphological subtypes of acute nonlymphocytic leukemia (ANLL) were investigated and were usually found to have increased levels of F1 + 2, TAT, and FPA at clinical presentation. However, the magnitude of the elevations was considerably greater and the correlation between TAT and FPA levels was stronger in APL than in ANLL. These studies provide direct evidence that patients with APL, as well as ANLL, generate excessive amounts of thrombin within their vascular system. Furthermore, the data suggest that the concentrations of F1 + 2, compared with the levels of FPA, may be a more sensitive indicator of hemostatic system hyperactivity in individuals with DIC.