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Introduction: Prosthetic valve thrombosis (PVT) is a serious complication seen with mechanical prosthetic cardiac valves and is associated with high mortality. Emergency surgery (thrombectomy or valve replacement) had been the traditional treatment, but now with intravenous thrombolytic therapy as an alternative to emergency surgery in patients with PVT has shown excellent success rate and acceptable risk. This study is aimed to determine efficacy and safety of use of thrombolytic agents (tPA or STK) in patients with PVT. Materials and Methods: This was a retrospective, single-center study of patients with PVT admitted between 2004 and 2020 at a tertiary care center in North India. The diagnosis of PVT was based on a history of prosthetic heart valve replacement, clinical presentation, and by diagnostic methods. All patients received either tenecteplase or streptokinase given as a bolus dose of 2.5 lac units over ½ h, followed by 1 lac units/h for 24-48 h depending on clinical response and complication, whereas tenecteplase (1 mg/kg of body weight) was given as bolus. Results: Of 72 patients, 45 patients received t-PA as a thrombolytic drug. Complete success was obtained in 39 patients (86.66%), whereas partial success in 3 (17.77%) and failure in 3 (6.66%). Among the patients who received streptokinase (n = 27), complete success was found in 23 patients (85.19%), whereas partial success was seen in 3 (11.11%) and failure was seen in 1 patient (3.7%). Conclusion: Thrombolysis is a reasonable option in patients with PVT. Our study has reiterated that major factors for PVT are warfarin poor compliance and subtherapeutic international normalized ratio. Postclosure clinical follow-up along with patient education should be followed in patients with mechanical prosthetic valve. [ABSTRACT FROM AUTHOR]