Background: Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to be efficacious to prevent pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). However, the target patients, the type of NSAID, the route of administration and the time of drug delivery remain unclear, as well as the potential efficacy in reducing the severity of pancreatitis, length of hospital stay and mortality. The objective of the study was to evaluate these questions by performing a systematic review and meta-analysis. Methods: Multiple searches were performed in the main databases. Randomized controlled trials (RCTs) comparing NSAIDs vs. placebo in the prevention of post-ERCP pancreatitis were included. Primary endpoint of the study was the efficacy for pancreatitis prevention. Sub-analyses were performed to determine the risk reduction in high and low risk patients, and to define optimal time, route of administration, and type of NSAID. Secondary endpoints were safety, moderate to severe pancreatitis prevention and reduction of hospital stay and mortality. Results: Nine RCTs enrolling 2133 patients were included. The risk of pancreatitis was lower in the NSAID group than in the placebo group (RR 0.51; 95%CI 0.39-0.66). The number needed to treat was 14. The risk of moderate to severe pancreatitis was also lower in the NSAID group. (RR 0.46; 95%CI 0.28-0.76). No adverse events related to NSAID use were reported. NSAIDs were effective in both high-risk and unselected patients (RR 0.53; 95%CI 0.30-0.93 and RR 0.57; 95%CI 0.37-0.88). In the subanalyses, only rectal administration of either indomethacin (RR 0.54; 95%CI 0.38-0.75) or diclofenac (RR 0.42; 95%CI 0.21-0.84) was shown to be effective. There were not enough data to perform a meta-analysis in hospital stay reduction. No deaths occurred. Conclusion: A single rectal dose of indomethacin or diclofenac before or immediately after ERCP is safe and prevents procedure-related pancreatitis both in high risk and in unselected patients. © 2014 Puig et al.