Aims Left atrial appendage (LAA) occlusion with first generation Ultraseal device (Cardia, Eagan, Minnesota) has been shown to be a feasible therapeutic option in patients with non-valvular atrial fibrillation (NVAF). However, there is a paucity of data regarding the novel Ultraseal device. To assess feasibility and safety of second generation LAA closure Ultraseal device in patients with NVAF. Methods and results All patients with NVAF undergoing second generation Ultraseal device implantation between February 2018 and September 2020 were included in a multicentre international registry. Periprocedural and post-discharge events were collected up to 6-months follow-up. Primary efficacy endpoints of interest were device success and technical success; primary safety endpoint was in-hospital major adverse events occurrence. A total of 52 patients were included: mean age 75 ± 8, 69.2% male, mean HAS-BLED 3 ± 1. The device was successfully implanted in all patients. Technical success was achieved in 51 patients (98.0%). In-hospital major adverse event occurred in three patients (5.8%). The incidence of 6-months all-cause death and major bleeding was 11.6% and 2.1%, respectively. No strokes, transient ischaemic attacks, systemic embolisms or device embolization were reported. Conclusions Second generation Ultraseal Device implantation was associated with high procedural success rate and a low incidence of peri-procedural complications. Larger studies with longer follow-up are warranted to evaluate the safety and the efficacy of this device, especially at medium and long term follow-up.