Prophylaxis is important for post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP), which is the most common and serious complication of ERCP. Although the current guidelines include independent patient- and procedure-related risk factors for PEP and available PEP prophylactic measures, the synergistic effect of these risk factors on PEP should also be considered, given that patients often harbor multiple risk factors. Furthermore, a combination of prophylactic measures is often selected in clinical practice. However, established methods estimating the synergistic effect of independent risk factors on PEP incidence are lacking, and evidence on the impact of combining prophylactic measures on PEP should be discussed. Selection of appropriate candidate patients for ERCP is also important to reduce the incidence of PEP associated with unnecessary ERCP. ERCP indications in patients with asymptomatic common bile duct stones (CBDSs) and in those with suspected CBDSs with no imaging-based evidence of stones are controversial. Further studies are warranted to predict the synergistic effect of independent risk factors on PEP, determine the best prophylactic PEP measures, and identify appropriate candidates for ERCP in patients with asymptomatic CBDSs and those with suspected CBDSs.