Background <p>Peptic ulcer disease (PUD) remains a significant public health concern globally, particularly in regions with high prevalence of risk factors such as Helicobacter pylori infection and Non-Steroidal Anti-Inflammatory Drug (NSAID) use. This study aimed to investigate the prevalence of PUD and its associated risk factors among hospitalized patients in a tertiary hospital in southwest Iran.</p> Methods <p>A mixed-methods design was employed, including a comprehensive literature review, checklist development and validation via a modified Delphi process, a cross-sectional prevalence study, and a hospital-based case-control study. Data were collected from 43,324 patient records (2019–2023) at Abadan University Teaching Hospital. Risk factors were assessed using a validated 21-item checklist, and multivariate logistic regression was used to identify independent predictors of PUD.</p> Results <p>Among all admissions, 6,874 cases of PUD were identified, indicating a point prevalence of 15.9% (95% CI: 15.6–16.2). NSAID use (75.3%), H. pylori infection (70.1%), smoking (46.9%), and corticosteroid use (30.2%) were highly prevalent among PUD patients. Significant independent risk factors included age ≥ 60 years (AOR: 1.65), NSAID use (AOR: 2.58), H. pylori positivity (AOR: 2.41), smoking (AOR: 1.45), and ulcer size ≥ 5&#xa0;mm (AOR: 2.19). Despite the high rate of NSAID use, only 26.4% received gastroprotective therapy.</p> Conclusions <p>The findings underscore the high burden of PUD in hospitalized patients in southwest Iran, with modifiable risk factors such as NSAID use, H. pylori infection, and smoking playing a critical role. Targeted interventions, including Proton Pump Inhibitor (PPI) co-prescription, H. pylori eradication, and lifestyle modifications, are essential to reduce PUD incidence and its complications.</p> Graphical abstract <p>The presented figure 1 provides a graphical abstract summarizing the main findings of this study.</p> <p></p>