We evaluated both the safety and efficacy of reteplase for treatment of acute arterial occlusion as well as outcomes based on treatment of the underlying lesion. From November 2000 to February 2004, reteplase was used to treat arterial occlusions in 81 patients. Catheter-directed intrathrombus thrombolysis was performed with reteplase (0.5 units/hr) continuous infusion. Percutaneous mechanical thrombectomy (Angiojet) was performed in 61% (n = 50) of patients prior to thrombolysis. Unmasking of significant lesions resulted in endovascular intervention (39.5%), open surgical repair (24.6%), or both endovascular and surgical repair (9.8%) of the lesion. No lesion was found in 25.9% of patients. Major and minor complication rates as well as restoration of patency, limb salvage, and amputation-free survival were evaluated. Eighty-one patients received reteplase therapy (median = 10.3 +/- 5.3 units, 19.5 +/- 7.4 hr) followed by next-day arteriogram to assess thrombus removal. Technical success was achieved in 96.2% (n = 78) of cases. Kaplan-Meier life table analysis revealed overall primary patency rates of 76.3%, 60.1%, and 51.6%, at 1, 6, and 12 months, respectively. Overall amputation-free survival rates were 86.4%, 76.4%, and 69.7% at 1, 6, and 12 months, respectively. When subdivided into postlysis intervention, the lysis-only group achieved increased patency (p = 0.0143) and increased limb salvage (p = 0.0219) at 1 year compared to the lysis and endovascular intervention and the lysis and surgical groups. The 30-day complication rate was 17.3% (n = 14), with a major complication rate of 4.9% (n = 4) and a minor complication rate of 12.3% (n = 10). There were no intracranial hemorrhagic complications. Intra-arterial catheter-directed infusion of reteplase for acute lower extremity ischemia is safe and efficacious, as shown by the low risk of bleeding complications, high limb salvage rates, and low mortality rates in this study. The complexity of the lesion that is unmasked through thrombolytic therapy is a predictor of patency and limb salvage.