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Introduction: Acute necrotizing pancreatitis (ANP) carries a mortality rate of up to 15%. The American Gastroenterological Association recommends antibiotics only in confirmed or strongly suspected infection. Utilizing a large real-world database, this study investigated whether antibiotic administration for ANP is associated with mortality or other complications. It was hypothesized that antibiotics would not confer protective benefit against systemic complications and death. Methods: We performed a retrospective study utilizing the TriNetX hybrid data registry which aggregates 156 healthcare organizations and 130 million patients. Adults (≥18 years) with a diagnosis of infected or uninfected ANP were identified using ICD-10 codes. Patients with concurrent infections were excluded. Cohorts were defined by the presence (+Abx) or absence of antibiotic (-Abx) exposure within 48 hours of ANP diagnosis. The primary outcome was 30-day mortality. Secondary outcomes included incidence of hemodialysis, pancreatic debridement and vasopressor use. Sample size calculation suggested a sample of 350 patients to detect a difference of 10% in mortality. Propensity score–matching (PSM) and outcome analyses were performed using built-in TriNetX analytics tools, with results reported as risk differences (RD), 95% confidence intervals (CI), and p-values. Results: A total of 4272 patients were included following PSM. There were no significant differences in demographics or comorbidities between cohorts. Mortality rate for +Abx group (7.1%) was higher than -Abx group (2.9%; RD -4.2%, 95% CI -0.055,-0.029; p< 0.001). +Abx group was associated with significantly higher rates of hemodialysis (2.7% vs. 0.5%, RD -2.2%, 95% CI -0.030, -0.015; p< 0.001), vasopressor requirements (25.6% vs. 12.2%, RD -13.4%, 95% CI -0.157, -0.111; p< 0.001), and bacteremia (2.7% vs. 1.0%, RD -1.7%, 95% CI -0.025, -0.009; p< 0.001). No significant differences were observed in rates of debridement. Conclusions: In this propensity matched cohort of patients with necrotizing pancreatitis, antibiotic administration was associated with higher mortality, dialysis, bacteremia and vasopressor requirements. These findings may reflect greater baseline illness severity among +Abx patients. Further studies are warranted to explore these observations.