The pharmacokinetics of recombinant human tissue-type plasminogen activator (rt-PA) were studied in 20 subjects during and after its i.v. infusion at three different rates (5.6, 8.3, and 10 micrograms/kg/min). Steady-state plasma concentrations of 0.9 to 1.6 micrograms/ml were reached. The plasma disappearance curves of rt-PA (both antigen and activity) after cessation of infusion were approximated by a sum of two exponential terms and the turnover of rt-PA was represented by a two-compartment mammillary model with peripheral (liver) elimination. The fractional efflux rate constant from the central compartment was 0.10 per min and the fractional catabolic rate constant about 0.02 per min. After cessation of infusion the initial half-life of the drug in plasma was 6 min. Fibrinogen levels were measured by a clotting rate assay and by sodium sulfite precipitation. Infusion of rt-PA at 10 micrograms/kg/min for 30 min did not cause systemic fibrinogen breakdown. Infusion of 5.6 micrograms/kg/min for 90 min was associated with a decrease of fibrinogen to 62% of the preinfusion value (4.5 g/l) as measured with the clotting rate assay, but only 2% was recovered as incoagulable fibrinogen-fibrin degradation products. Infusion of 8.3 micrograms/kg/min for 90 min resulted in a decrease of fibrinogen to 45% of the preinfusion level (2.5 g/l) and generation of 8.5% fibrinogen-fibrin degradation products. Fibrinogen assays with the sodium sulfite method showed a much less extensive decrease of fibrinogen. This extent of systemic fibrinolytic activation and fibrinogen breakdown at high infusion rates and prolonged durations is compatible with that anticipated from the kinetic parameters of the activation of plasminogen by rt-PA.