Thrombolysis is an essential first step in the surgical management of acute spontaneous axillo-subclavian vein thrombosis (Paget-Schroetter syndrome). During the past decade, Urokinase became the standard thrombolytic agent until temporarily withdrawn from the market. In its absence, recombinant tissue plasminogen activator (r-TPA) was introduced and attained widespread use. A direct comparison of the efficacy of these two agents in this setting has not been published. The goal of this study is to compare thrombolytic agents in the management of acute Paget-Schroetter syndrome. This study is based on a retrospective review of 30 consecutive patients (15 Urokinase, 15 r-TPA) who underwent thrombolysis and surgery for Paget-Schroetter syndrome. Our hypothesis is that thromblysis with Urokinase and r-TPA is equally safe and effective in management of acute axillo-subclavian vein thrombosis. Primary outcome measures include success of lysis, hemorrhagic complications, subclavian vein patency at completion of treatment, resolution of presenting symptoms, and restitution of normal arm function. There were no significant differences in the primary outcome measures: success of lysis, hemorrhagic complication, perioperative bleeding, and subclavian vein patency. Time to completion of lysis was slightly shorter with r-TPA (but this did not achieve statistical significance). One patient in each group suffered incomplete lysis of thrombus. One patient in the r-TPA group required transfusion due to surgical bleeding. No patient received transfusion due to thrombolysis-related bleeding. All patients experienced resolution of symptoms and return of arm function. Our findings support the hypothesis that Urokinase and r-TPA are similarly safe and successful for management of spontaneous axillo-subclavian vein thrombosis. Given these results, secondary factors such as cost, availability, and familiarity with the different agents will likely determine the agent of choice.