The purpose of our study was to assess the efficacy of external ultrasound to enhance in vitro thrombolysis with urokinase or streptokinase. One-hour-, 1-day-, 4-day-, and 6-day-old human blood thrombi (n = 366) were incubated in normal saline solution with three different concentrations of streptokinase (50, 250, and 2000 mu/ml) or urokinase (200, 2000, and 5000 mu/ml). Thrombi were exposed to pulsed ultrasound of 1 MHz at 1.0, 1.5 and 2.2 W/cm2 at different exposure times. The combination of ultrasound (2.2 W/cm2, 30 min) and urokinase or streptokinase enhanced lysis rate by an average of 25% compared with lysis with thrombolytic agents alone (p < 0.05). The enhancement was greater at higher ultrasound power outputs (2.2 W/cm2 > 1.5 W/cm2 > 1.0 W/cm2). At higher-power outputs there was no increase of temperature in the solution containing the thrombus. The extent of lysis was higher with longer ultrasound exposure time and with fresh thrombi. These data suggest that use of external ultrasound has the potential to increase both efficacy and rate of thrombolysis.