Background: Acute limb ischemia occurs in approximately 150,000 patients and could lead to serious morbidity including need for amputation. Development of effective catheter-based therapies for acute limb ischemia requires adequate in vivo testing. There is clearly a need for a large animal model for effective in vivo testing of intra-arterial thrombolytics and distal embolic protection devices to be used in the treatment of acute limb ischemia. Methods: Institutional Animal Care and Usage Committee approval was obtained. Transarterial transfemoral biplane digital subtraction angiography was performed in a 95-lb Yorkshire swine under anesthesia. Quantitative measurement of vessel diameters in swine was performed to select vessels that mimic human infrapopliteal vessels. Intra-arterial injection (over 30 s) of 20 U (2054 NIH U/mg) of porcine thrombin was used to create a sitespecific clot under transient flow arrest (1 min) using a nondetachable balloon catheter. Intra-arterial thrombolysis was performed using 1 mg (2.09 mg/ml) of human plasmin. Serial angiography was performed to assess the stability of the clot as well as the response to intra-arterial thrombolysis. Results: Peripheral arterial diameters in swine ranged from 1.65 to 4.8 mm: external iliac (4.8 mm), common femoral (3.4 mm), infrapopliteal (3.03 mm), deep femoral (2.58 mm), geniculate (1.79 mm), tibial (1.91 mm), and dorsalis pedis (1.65 mm). Serial angiography after injection of porcine thrombin revealed occluded infrapopliteal artery exhibiting rapid onset of clot development (2.5 min) and its mechanical stability (30 min). SHELTER, a novel distal embolic protection device, was safely deployed distal to the clot and intra-arterial thrombolysis was performed. Follow-up angiography revealed partial revascularization. The embolic protection device was safely removed. Conclusion: This large animal porcine model allows for using a sitespecific, reliable, and rapid method of creation and lysis of blood clots within the small peripheral vessels and could be useful in the development and preclinical evaluation of catheter-based endovascular therapies for acute limb ischemia.