Background <p>Given the evidence that poor glycemic control is associated with immunological dysfunction, serum glycosylated hemoglobin A1c (HbA1c), as a useful indicator reflecting blood glucose homeostasis, has potential to predict infectious complications. In this study, we aimed to explore the association between poor glycemic control (HbA1c ≥ 6.5 as an indicator) and infected pancreatic necrosis (IPN) in patients with acute necrotizing pancreatitis (ANP).</p> Methods <p>This is a secondary analysis of pooled data from the TRACE trial and a retrospective single-center cohort, involving ANP patients admitted within 72&#xa0;h after onset of abdominal pain between March 2017 and October 2022. Patients had no HbA1c data at enrollment/admission were excluded. The Multivariable Cox proportional hazards regression (MCPHR) model was used to assess the association between poor glycemic control and 90-day IPN. Mediation analyses were used to define the relationships between the independent variables and 90-day IPN.</p> Results <p>A total of 153 patients were enrolled, of whom 20.3% (31/153) patients developed IPN within 90 days. Most patients with IPN had HbA1c ≥ 6.5% at admission (25/31, 80.6%), compared to 38.5% (47/122) in the non-IPN patients. In the MCPHR model, HbA1c ≥ 6.5% [HR (95%CI) = 4.10 (1.42–11.90); <i>p</i> = 0.009], SOFA score on admission [HR (95%CI) = 1.47 (1.26–1.70); <i>p</i> &lt; 0.001] and pancreatic necrosis extent &gt; 50% [HR (95%CI) = 3.15 (1.06–9.35); <i>p</i> = 0.039] were independent risk factors for 90-day IPN. In addition, patients with HbA1c ≥ 6.5% experienced a higher incidence of hyperglycemia during the first week of enrollment [RR (95%CI) = 9.19 (4.23–19.95); <i>p</i> &lt; 0.001]. Mediation analyses showed that the presence of hyperglycemia completely mediated the association between HbA1c ≥ 6.5% and 90-day IPN.</p> Conclusion <p>Among ANP patients, HbA1c ≥ 6.5% was associated with the development of IPN. The mediation effect of hyperglycemia may explain it.</p>