Histotripsy is a noninvasive therapeutic technique that uses ultrasound generated from outside the body to create controlled cavitation in targeted tissue, and fractionates it into acellular debris. We have developed a new histotripsy approach, termed microtripsy, to improve targeting accuracy and to avoid collateral tissue damage. This in vivo study evaluates the safety and efficacy of microtripsy for noninvasive thrombolysis in a porcine deep vein thrombosis (DVT) model. Acute thrombi were formed in left femoral veins of pigs (~35 kg) by occluding the vessel using two balloon catheters and infusing with thrombin. Guided by real-time ultrasound imaging, microtripsy thrombolysis treatment was conducted in 14 pigs. 10 pigs were euthanized on the same day (acute) and 4 at 2 weeks (subacute). To evaluate vessel damage, 30-min free-flow treatment in right femoral vein (no thrombus) was also conducted in 8 acute pigs. Blood flow was successfully restored or significantly increased after treatment in 13 out of the 14 pigs. The flow channels reopened by microtripsy had a diameter up to 64% of the vessel diameter (~6 mm). The average treatment time was 16 minute per cm-long thrombus. Only mild intravascular hemolysis was induced during microtripsy thrombolysis. No damage was observed on vessel walls after two weeks of recovery, venous valves were preserved, and there was no sign of pulmonary embolism. The results of this study indicate that microtripsy has the potential to be a safe and effective treatment for DVT in a porcine model.