Coagulation and fibrinolysis were studied in patients with acute myocardial infarction during intravenous infusion of recombinant human tissue-type plasminogen activator (rt-PA) (0.75 mg/kg over 90 min, n = 101), streptokinase (1,500,000 IU over 60 min, n = 61), or placebo (n = 40). In the rt-PA group, the plasma level of rt-PA antigen was 1.2 ± 0.6 gig/ml (mean ± SD) and the euglobulin fibrinolytic activity (EFA) was 910 735 IU t-PA/ml. In the streptokinase group, the EFA was equivalent to 430 ± 435 IU t-PA/ml. At the end of the infusion, the plasma fibrinogen level measured with a coagulation rate assay was decreased to 57 ± 33% of the preinfusion value in the rt-PA group, to 7 ± 10% in the streptokinase group, and remained unchanged in the placebo group. Fibrinogen-fibrin degradation products increased to 0.75 ± 0.54 mg/ml in the streptokinase group but to only 0.10 ± 0.13 mg/ml in the rt-PA group. The plasma levels of a2-antiplasmin, plasminogen, and factor V decreased to between 30% and 45% in the rt-PA group but significantly more in the streptokinase group (to between 15% and 25%). Thus rt-PA induced much less systemic fibrinolytic activation than streptokinase. In the patients who received rt-PA, a weak correlation (r = .21, n = 89, .1 > p > .05) was found between the extent of fibrinogen breakdown at 90 min and the plasma rt-PA concentration. Fibrinogen breakdown was significantly higher (p < .05) in patients with successful recanalization (decrease to 52 ± 32%, n = 61) than in unresponsive patients (decrease to 69 ± 35%, n = 22). The plasma rt-PA concentration in patients with successful recanalization was 1.4 ± 0.7 gg/ml, and that in unresponsive patients was 1.1 ± 0.7 μ/ml (p > .1).