Objective Acute pancreatitis with walled-off necrosis (WON) is associated with considerable morbidity and mortality. Previous studies have evaluated outcomes in WON collections of limited size, while data about large WON with long-term follow-up are lacking. We aimed to report our experience in managing large WON. Methods Between 2010 and 2020, consecutive patients with large (>15 cm) WON were identified from a prospectively maintained database. Patients with chronic pancreatitis or an index intervention 90 days or more from the debut of symptoms were excluded. We registered clinical and technical outcomes following minimally invasive treatment in WON >15 cm. Follow-up was a minimum of 1 year. Results Overall, 144 patients with WON >15 cm, with a median age of 60 (interquartile range [IQR] 49-69) years, were included. The median WON size was 19.2 cm (IQR 16.8-22.1). Most patients were treated with endoscopic transluminal drainage (93%). The median length of stay was 53 days (IQR 39-76) and 61 (42%) patients needed intensive care support during their hospital stay. As 143 patients (99%) were managed using endoscopic or video-assisted retroperitoneal techniques, only one (0.7%) patient needed an open necrosectomy. Procedure-related adverse events occurred in 10 (7%) patients. Overall, 24 patients (17%) died during admission, all due to multiorgan failure. The median follow-up was 35 months (IQR 15-63.5). Complete resolution was achieved in all remaining patients. Conclusion Minimally invasive treatment of large WON is feasible, with a minimal need for surgery and acceptable rates of morbidity and mortality.