Deep vein thrombosis (DVT), clot formation in the deep veins in the legs, affects two million Americans annually. Clinical DVT treatments include thrombolytic drugs and catheter-based surgical procedures. Both methods have significant drawbacks, such as excessive bleeding and invasiveness. Guided by ultrasound imaging, histotripsy is a non-invasive cavitation-based ultrasound therapy that fractionates tissue. Using our laboratory prototype, histotripsy fractionated in vitro clots into debris smaller than red blood cells at a speed an order of magnitude faster than clinical thrombolysis methods. Using an in vivo porcine DVT model, histotripsy non-invasively eradicated the thrombus in 10 of 12 cases. We have designed and constructed an integrated ultrasound image-guided histotripsy thrombolysis system based on human DVT patient data. We propose a comprehensive pre-clinical study to determine the safety and efficacy of this clinically designed histotripsy system in a porcine DVT model. The proposed study is critical to advancing the clinical translation of this new technology to improve the standard of care for DVT patients.