Objective: To investigate the surgical treatment strategies for wall-off pancreatic necrosis (WOPN) with multi-drug resistance organisms (MDRO) infections. Methods: The clinical data of 57 WOPN patients with clear pathogenic evidence treated between October 2010 and June 2016 were retrospectively analyzed, and the treatment and outcomes of 35 cases with MDRO infections among them were independently summarized. Results: The mortality in the entire group of patients was 29.8% (17/57), which in patients with MDRO infections was 40.0% (14/35) and in those with common bacterial infections was 13.6% (3/22), and the difference had statistical significance (P<0.05). In patients with MDRO infections compared with patients with common bacterial infections, the severity of acute pancreatitis was aggravated, number of surgical interventions was increased, length of ICU stay was prolonged and hospitalization cost was increased (all P<0.05). Fifty patients (87.7%) received step-up surgical treatment with initial percutaneous catheter drainage (PCD) , followed by minimal access retroperitoneal pancreatic necrosectomy (MARPN) or open pancreatic necrosectomy (OPN) if necessary, and the overall cure rate was 72.0% and the cure rate in cases with MDRO infections was 60.6%; 7 patients (12.3%) underwent step-down surgical treatment with initial OPN directly, or combined with PCD and MARPN later, and the overall cure rate was 71.4% and the cure rate in cases with MDRO infections was 50.0%. A total of 50 MDRO pathogens were detected in the whole group of patients and the top five commonest pathogens were MDR-Acinetobacterbaumanni (36.0%, 18/50), MDR-Klebsiella pneumonia (20.0%,10/50), Escherichia coli with extended-spectrum β-lactamases (14.0%, 7/50), MDR-Pseudomonas aeruginosa (10.0%, 5/50) and MDR-Enterobacter cloacae (8.0%, 4/50), respectively. Conclusion: Step-up strategy is the first choice for WOPN, and those with MDRO infections may have unfavorable outcomes, for whom, more aggressive surgical treatment strategies are always required.