AIM: Periampullary diverticulum (PAD) is a common anatomical variant that can potentially impact the technical difficulty and outcomes of endoscopic retrograde cholangiopancreatography (ERCP), necessitating a comprehensive understanding of its effects on the procedure. To evaluate the effect of PAD subtypes and diameter on ERCP cannulation success and clinical outcomes. MATERIALS AND METHODS: The study included patients with PAD and papilla-naïve patients undergoing ERCP for suspected common bile duct stones or distal benign strictures (due to PAD compression). PAD subtyping was based on Lobo and Li-Tanaka classifications. Diverticulum size was categorized as small (<
1 cm), medium (1-2 cm), and giant (≥2 cm). RESULTS: Of the 907 patients analyzed, 164 (18%) had PAD with a median age of 63 years. PAD patients were significantly older than non-PAD patients and had more comorbidities . The most frequent PAD type was 2B (34.1%) based on the Li-Tanaka classification. Subgroup analysis of PAD types 1, 2, 3, and 4 showed no statistically significant differences in cannulation time, success, total procedure time, or adverse events (AEs). . Overall cannulation success rates were similar between PAD and non-PAD groups (99.4% vs 99.6%). Analysis based on diverticulum size revealed higher probabilities of giant stones and procedure-related AEs in giant diverticula. The risk of post-ERCP pancreatitis was notably low at 1.8% in the PAD group. CONCLUSION: Diverticulum size, rather than PAD subtype, may be more closely associated with cannulation success and procedure-related AEs in ERCP. Individualized management considering diverticulum size may improve outcomes in PAD patients undergoing ERCP.