We performed this study to evaluate the efficacy of catheter-directed thrombolysis with urokinase in treating acute symptomatic iliofemoral deep venous thrombosis associated with protein C and/or S deficiency. A total of 42 consecutive patients with deep venous thrombosis were seen between September 2000 and August 2002. Of these, catheter-directed thrombolysis via the popliteal vein was performed in 5 patients (11.9%) with acute iliofemoral deep venous thrombosis associated with protein C and/or S deficiency. Average duration of symptoms was 4.2 days (range, 1-7 days). The average urokinase dose was 2.7 million IU (range, 0.6 million to 7.0 million IU) infused over an average of 33.1 h (range, 16-67 h). Lysis was complete in all five treated cases. Two cases had underlying iliac venous stenoses (>50%) that were treated with angioplasty and stent placement. In one patient in whom recanalization of a right iliac vein occlusion was successful, thrombosis occurred in the treated vein within 3 weeks of intervention despite full anticoagulation therapy, and further intervention was required. There were no complications or clinically detectable pulmonary emboli. The technical and clinical success rates were 100%. This initial experience suggests that catheter-directed thrombolysis for treatment of acute symptomatic iliofemoral deep venous thrombosis associated with protein C and/or S deficiency is safe and effective.