Transcatheter paravalvular leak closure (TPVLC) offers a viable alternative to reoperation but optimal technical strategy is still to be defined. We present a prospective TPVLC registry in which safety and efficacy of multi-plug, single-stage approach were assessed. Patients with heart failure (HF) symptoms caused by PVL were qualified for TPVLC by Heart Team. Ante- or retrograde access was employed for mitral while retrograde only for aortic PVLs. Two to 4 AVP 3 devices were simultaneously implanted into each PVL. Endpoints were defined according to VARC-2. From 64 referred patients 49, with either mechanical valves (n = 30) or stented bioprostheses, were eligible for TPVLC. PVL location was mitral (n = 29) or aortic (n = 20). In aortic group acute procedural success (APS) ratio was 100% and no MACCEs occurred. In mitral group, first-attempt TPVLC was successful in 22 cases (4/4 in transapical and 18/25 in transseptal access). Second-attempt transapical procedure followed transseptal failure in 5 patients. Mitral TPVLC ultimately proved efficient in 89.7% with 76.5% APS. Cumulatively, TPVLC was accomplished in 46 subjects (93.9%) with 78% APS. When successful, it led to a significant decrease of NT-proBNP concentration and HF symptoms regression. Periprocedural safety endpoints were met in three patients and included non-disabling stroke, and two access site-related complications. In device failure group two patients died (end-stage HF) and two others were rehospitalized. TPVLC with simultaneous deployment of multiple AVP III occluders is feasible with high device success rate and no significant periprocedural complications. The clinical benefits of reduction of HF symptoms and hemolysis are evident after 30 days and persist up to 1 year without recurrence of PVL.