Background and Aims The occurrence of duodenal fistula following infected pancreatic necrosis (IPN) in the later stage of treatment for acute necrotizing pancreatitis presents a significant clinical challenge. It often leads to severe complications such as difficulty in administering enteral nutrition, electrolyte imbalances, abdominal bleeding, and worsening infections. This study was performed to explore the efficacy of enteral nutrition combined with step-up drainage in treating IPN complicated by duodenal fistula and to share single-center experience.Methods The clinical data of 66 patients with IPN complicated by duodenal fistula who underwent enteral nutrition combined with step-up drainage in the Severe Pancreatitis Treatment Center of the Nanjing Eastern Theater General Hospital between January 2018 and December 2020 were retrospectively analyzed.Results Among the 66 patients, the median time from disease onset to the development of duodenal fistula was 53 (32-75) d. In 46 cases (69.7%), suspicious digestive fluid-like discharge was observed from drainage tube or double-lumen tube. The diagnosis and location of the duodenal fistula were confirmed in 49 patients (74.2%) through fistulography, while the remaining cases were confirmed via surgical exploration or endoscopy. The duodenal fistulas were mainly located in the horizontal part (33.3%) or descending part (50.0%) of the duodenum. Nutritional access was safely established through nasojejunal tube in 61 patients (92.4%), while 5 patients (7.6%) required surgery to establish the access. Twenty patients (30.3%) experienced secondary abdominal bleeding, and 14 patients (21.2%) died. Among the 52 patients who recovered, 49 (94.2%) healed through step-up drainage, while 3 (5.8%) required surgery due to delayed healing. Of the 49 patients who underwent non-surgical treatment, 10 (20.4%) achieved fistula closure through drainage tube, and 39 (79.6%) achieved closure through continuous lavage drainage via double-lumen tube. The median healing time for duodenal fistula in non-surgically treated patients was 41 (29-80) d.Conclusion Patients with IPN complicated by duodenal fistula are in a critical condition. Enteral nutrition combined with step-up drainage is an effective treatment for these patients.