Background. Although periampullary diverticulum is usually asymptomatic and discovered incidentally in patients during endoscopic retrograde cholangiopancreatography (ERCP), it may lead to post-ERCP morbidity. We compared baseline characteristics and clinical data as well as ERCP results in patients with and without periampullary diverticulum. Methods. Clinical, laboratory, and ERCP data of 780 patients referred to the Taleghani Hospital, as a great referral endoscopy center, in Iran were prospectively analyzed. Results. The periampullary diverticulum was identified in 44 patients (5.6%). Cannulation of common bile duct was more failed in patients with diverticulum compared to others (35.5% versus 11.5, P < 0.001). Patients with diverticulum had eight times more often common bile duct stone compared to patients without diverticulum (54.5% versus 12.2%, P < 0.001). Post-ERCP complications were observed in 2.3% and 4.2% of patients with and without diverticulum, respectively, which did not significantly differ in both groups. Conclusion. Because of more failure cannulation in the presence of periampullary diverticulum, ERCP requires more skills in these patients. Prevalence of common bile duct stone was notably higher in patients with diverticulum; therefore, more assessment of bile stone and its complications in these patients is persistently recommended.