Clinically available thrombolysis techniques are limited by either slow reperfusion (drugs) or invasiveness (catheters) and carry significant risks of bleeding. In this study, the feasibility of using histotripsy as an efficient and noninvasive thrombolysis technique was investigated. Histotripsy fractionates soft tissue through controlled cavitation using focused, short, high-intensity ultrasound pulses. In vitro blood clots formed from fresh canine blood were treated by histotripsy. The treatment was applied using a focused 1-MHz transducer, with five-cycle pulses at a pulse repetition rate of 1kHz. Acoustic pressures varying from 2 to 12MPa peak negative pressure were tested. Our results show that histotripsy can perform effective thrombolysis with ultrasound energy alone. Histotripsy thrombolysis only occurred at peak negative pressure >or=6MPa when initiation of a cavitating bubble cloud was detected using acoustic backscatter monitoring. Blood clots weighing 330mg were completely broken down by histotripsy in 1.5 to 5min. The clot was fractionated to debris with >96% weight smaller than 5mum diameter. Histotripsy thrombolysis treatment remained effective under a fast, pulsating flow (a circulatory model) as well as in static saline. Additionally, we observed that fluid flow generated by a cavitation cloud can attract, trap and further break down clot fragments. This phenomenon may provide a noninvasive method to filter and eliminate hazardous emboli during thrombolysis.