Background and Aims In high-risk surgical patients, the treatment of choice of acute cholecystitis is percutaneous transhepatic gallbladder drainage (PTGBD). Recently, a novel endoscopic device containing a lumen-apposing metal stent with an electrocautery (ECE-LAMS) on the tip has been developed. Methods High-risk surgical patients with acute cholecystitis who underwent EUS-guided gallbladder drainage (EUS-GBD) with the novel device were retrospectively retrieved from 7 tertiary care referral centers. Main endpoints were technical and clinical success rates, rate of procedural adverse events, and short- and long-term adverse events. Results Seventy-five patients (mean age, 75 ± 11 years; 36 men) underwent EUS-GBD. The procedure was technically and clinically successful in 98.7% and 95.9% of cases, respectively. Three patients without resolution of cholecystitis died, and 2 patients had procedure-related adverse events: 1 perforation requiring surgery and 1 major bleeding resolved conservatively. The mean follow-up for the entire cohort was 201 ± 226 days. Seven patients (9.6%) died within the first 30 days; 50 patients (71.4%) were alive at the last date of follow-up. Short- and long-term adverse events occurred in 6 patients: 3 had recurrent cholecystitis, 2 had migration of the stent, and 1 developed Bouveret syndrome, all managed nonsurgically. Overall, 8 adverse events (10.7%) occurred in the entire cohort of patients. Conclusions The novel ECE-LAMS for high-risk surgical patients with acute cholecystitis is safe, with a high technical and clinical success rate. Future multicenter studies comparing EUS-GBD versus PTGBD are warranted to determine which procedure is safer and clinically more effective for patients with high surgical risk acute cholecystitis.