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<b>Background:</b> Estimates suggest that 60,000-100,000 Americans die of Deep Vein Thrombosis / Pulmonary Embolism (DVT/PE) each year. Between 10 to 30% of people with PE will die within one month of diagnosis. Sudden death is the first symptom in about 25% of people who have PE. Among people who have had DVT, one third to one half will have long-term complications (post-thrombotic syndrome) such as swelling, pain, discoloration, and scaling in the affected limb. Microbubble (MB) enhanced sonothrombolysis (SL) has shown promise in treating vascular thrombosis, but MBs are micrometer-sized structures and do not easily permeate clots. We hypothesized that sub-micron structures, e.g., phase shift microbubbles (PSMB or nanodroplets, herein referred as MVT-101) would better permeate clots for more effective SL. We have already shown that MVT-101 (~250 nm in diameter size), easily penetrate the thrombus and demonstrate increased SL efficiency in the rat hindlimb model of microvascular obstruction (MVO). <b>Methods:</b> Bi-lateral occlusive model of DVT was created in the pigs. Endovascular ultrasound was delivered using the EKOS™ Endovascular System and transcutaneous ultrasound (TCUS) was delivered using a diagnostic transducer (GE Vivid E9). <b>Results:</b> We now report that in combination with the EKOS™ Endovascular System, MVT-101 made with perfluoropropane, dissolved occlusive DVT clots in a bi-lateral occlusive porcine model of DVT in combination with (Mean clot resolution = 45.12 ± 46.79 %) or without tissue Plasminogen Activator (tPA) (Mean clot resolution = 36.00 ± 52.27 %) within 60 min of treatment time. We also show that TCUS further SL was observed in the presence of MVT-101 and tPA (Mean clot resolution 76.21 ± 11.86 % with 1000-2000 mg tPA) as compared to tPA alone (Mean clot resolution 16.75 ± 17.00 % with 1000 mg tPA). <b>Conclusion:</b> Both procedures proved to be safe and did not produce PE. In conclusion, MVT-101 holds great potential as therapeutic agent for treating DVT either with TCUS or endovascular ultrasound (EVUS).