BACKGROUND: Acute pancreatitis is a major adverse event of endoscopic retrograde cholangiopancreatography (ERCP). Rectal administration of non-steroidal anti-inflammatory drugs (NSAIDs) decreases the incidence of post-ERCP pancreatitis (PEP). However, the efficacy of low dose rectal NSAIDs for preventing PEP remains controversial. METHODS: We performed a retrospective study of 301 patients with native papilla and a body weight of <50 kg who underwent ERCP between September 2010 and October 2019. After July 2016, a 25 mg dose of rectal diclofenac was routinely administered within 15 min before ERCP (NSAIDs group, n = 72) and the control group (n = 229) consisted of patients undergoing ERCP before this date without treatment. We compared the incidence of PEP between the two groups using propensity score matching. RESULTS: A total of 66 pairs of patients in each group were selected. The patients and procedural-related factors were similar in both groups. In total, 15 patients (11.4%) developed PEP: 12.1% (8/66) in the NSAIDs group and 10.6% (7/66) in the control group (Odds ratio (OR) 1.2; 95% confidence interval (CI) 0.4-3.5; P = 0.78). There was no significant difference in incidence of other adverse events related to ERCP between the two groups. CONCLUSIONS: Prophylactic administration of a 25 mg dose of rectal diclofenac did not reduce the incidence of PEP in patients with a native papilla and a body weight of <50 kg in this study and a certain dose of rectal NSAIDs, such as a 100-mg dose, should be administered regardless of body weight to prevent PEP.