Although the enhancement of tissue plasminogen activator (tPA) induced thrombolysis by ultrasound has been reported to be augmented by ultrasound contrast agents (UCA), few data exist regarding its process. The present study evaluated the effect of a galactose based UCA on the efficacy of ultrasonic enhancement of tPA thrombolysis and observed the serial changes in the acoustic property and histopathology. A catheter-type transducer capable of ultrasound emission in both continuous (CW) and pulsed wave (PW) was used. The tPA thrombolysis was studied in 30 artificial white thrombi, which were assigned to 4 study groups based on insonation modes and with and without UCA. Each sample was suspended in 100 ml saline in a beaker. Five minutes after tPA (8000 U) administration, ultrasound was applied for 10 min. For the UCA-treated groups, UCA (0.25 g) was added 5 min after the start of ultrasound exposure. The alteration of the thrombus was monitored with echography. Weight reduction of the thrombus was -25±6% in PW and -30±7% in CW, which was significantly enhanced by UCA treatment, -40±3% (p<0.005) in PW+UCA and -43±7% (p<0.005) in CW+UCA. The area of thrombus echo image minimally decreased with ultrasound alone (-12±6%: PW, -23±11%: CW). In the UCA groups, UCA induced a remarkable reduction of size (-36±3%: PW+UCA, -43±7%: CW+UCA) with a high-echo intensity in the superficial layer of the thrombus, where multiple cavity formation was observed by light microscope. UCA markedly enhanced the effect of ultrasound on tPA thrombolysis. The altered acoustic property and corresponding histological microcavity formation in the shallow layer within the thrombus suggests that UCA augmented infiltration of tPA into the thrombus. (Jpn Circ J 1999; 63: 478 - 484)