INTRODUCTION: Monitored anesthesia care (MAC) and general anesthesia (GA) are the two most common methods of sedation used for endoscopic retrograde cholangiopancreatography (ERCP). We performed systematic review and meta-analysis to compare the overall safety between MAC versus GA in ERCP. METHODS: We conducted a comprehensive search of multiple electronic databases and conference proceedings including PubMed, EMBASE, Web of Science databases, Google Scholar and manual search of references (from inception through May 2019) to identify the studies reporting use of MAC or GA as choice of sedation for ERCP. The primary outcome was to compare the overall sedation related side effects including hypoxia, arrhythmias, hypotension and aspiration in MAC versus GA groups. The secondary outcome was to study the total duration of procedure and recovery time. The meta-analysis was performed using Der Simonian and Laird random effect model. RESULTS: A total of 28 studies (11 in GA group and 18 in MAC group) reporting on 12918 patients were included. One study was included in both the groups. The mean age in both the groups was 60 years. A total of 27 studies reported sedation related side effects. The overall sedation related side effects were similar in GA (12.76%; 95% CI = 5.80–21.73, I2 = 95%) versus MAC (12.08%; 95% CI = 5.38–20.89, I2 = 99%) groups with P = 0.859 (Figure 1). In sub-group analysis, hypoxia, arrhythmias, hypotension, aspiration and other sedation related side effects were similar between the two groups (Table 1). The recovery time and duration of procedure was reported in 10 and 14 studies respectively. Although, the mean duration of procedure was more in MAC group (47 min versus 33 min) but mean recovery time was less as compared to GA group (47 min versus 59 min). Only 1.7% of the MAC patients were converted to GA. Significant heterogeneity was noted in in our meta-analysis. CONCLUSION: In our meta-analysis, overall sedation related side effects were similar between MAC versus GA groups. The mean duration of procedure was lower in GA group but on contrary recovery (mean) was noted to be faster in MAC group. Based on our meta-analysis, monitored anesthesia care could be used as an alternative to general anesthesia when performing ERCP, although high risk patients may be better served by general anesthesia. Large multicenter randomized control trials are needed to further validate our findings.