BACKGROUND Prosthetic valve thrombosis (PVT) is one of the life-threatening complications of prosthetic heart valve replacement. Due to the lack of randomized controlled trials, the optimal treatment of PVT remains controversial between thrombolytic therapy (TT) and surgery. OBJECTIVES This study aimed to prospectively evaluate the outcomes of TT and surgery as the first-line treatment strategy in patients with obstructive PVT. METHODS A total of 158 obstructive PVT patients (women: 103 [65.2%]; median age 49 years [IQR: 39-60 years]) were enrolled in this multicenter observational prospective study. TT was performed using slow (6 hours) and/or ultraslow (25 hours) infusion of low-dose tissue plasminogen activator (t-PA) (25 mg) mostly in repeated sessions. The primary endpoint of the study was 3-month mortality following TT or surgery. RESULTS The initial management strategy was TT in 83 (52.5%) patients and surgery in 75 (47.5%) cases. The success rate of TT was 90.4% with a median t-PA dose of 59 mg (IQR: 37.5-100 mg). The incidences of outcomes in surgery and TT groups were as follows: minor complications (29 [38.7%] and 7 [8.4%], respectively), major complications (31 [41.3%] and 5 [6%], respectively), and the 3-month mortality rate (14 [18.7%] and 2 [2.4%], respectively). CONCLUSIONS Low-dose and slow/ultraslow infusion of t-PA were associated with low complications and mortality and high success rates and should be considered as a viable treatment in patients with obstructive PVT. (J Am Coll Cardiol 2022;79:977-989) (c) 2022 by the American College of Cardiology Foundation.