Background/Aims: The combinatorial effects of prophylactic methods for postendoscopic retrograde cholangiopancreatography pancreatitis (PEP) in patients with risk factors remain unclear. In this network meta-analysis, we compared the efficacy of various prophylactic strategies to decrease the risk of PEP among patients with risk factors. Methods: A systematic review was performed to identify randomized controlled trials from PubMed, Embase, and the Cochrane Library through July 2021. We used frequentist network meta-analysis to compare the rates of PEP among patients who received prophylactic treatments as follows: class A, rectal nonsteroidal anti-inflammatory drugs; class B, prophylactic pancreatic stent; class C, aggressive hydration; or control, no prophylaxis or active control. We selected those studies that included patients with risk factors for PEP. Results: We identified 19 trials, comprising 4,328 participants. Class ABC (odds ratio [OR], 0.08; 95% confidence interval [CI], 0.03 to 0.24), class AC (OR, 0.10; 95% CI, 0.02 to 0.47), class AB (OR, 0.12; 95% CI, 0.05 to 0.26), class BC (OR, 0.13; 95% CI, 0.04 to 0.41), class A (OR, 0.16; 95% CI, 0.05 to 0.50), and class B (OR, 0.26; 95% CI, 0.14 to 0.46), were associated with a reduced risk of PEP as compared to that of the control. The most effective prophylaxis was ABC (0.87), followed by AC (0.68), AB (0.65), BC (0.56), A (0.49), and B (0.24) according to P-score. Conclusions The results of this network meta-analysis suggest that the more prophylactic methods are employed, the better the outcomes. It appears that for patients with risk factors, we need to prevent PEP through the use of these well proven combination strategies.