Background Guidewire (GW) cannulation can reduce the risk of post-ERCP pancreatitis (PEP) by avoiding the opacification of the main pancreatic duct. Objective To compare the effects of conventional contrast ERCP and GW cannulation of the common bile duct on the rate of PEP in low- and high-risk patients. Design Prospective, comparative-intervention single-center study. Setting Tertiary referral center. Patients Patients with biliary disease with an intact papilla were prospectively examined by ERCP. Interventions Biliary cannulation using a sphincterotome with contrast injection (ConI) or a hydrophilic GW without contrast injection. Main Outcome Measurements Pancreatitis rate in the GW group and the contrast injection (ConI) group. Results PEP occurred in 60 of 1249 patients (4.8%), 35 of 678 (5.2%) in the GW group and 25 of 571 (4.4%) in the ConI group (not significant). The overall rate of PEP was significantly higher in high-risk patients (12.2%) than in low-risk patients (3.5%) ( P < .001), but was similar for the 2 techniques within each of these 2 groups. In patients with unintended main pancreatic duct (MPD) cannulation or opacification, the rate of PEP was not significantly different with the GW (15.2%) and ConI (8.4%) techniques but was associated with a significantly higher rate of pancreatitis (11.9%) than in patients in whom the contrast medium or GW did not enter the MPD (3.5%) ( P < .001). Multivariate analysis indicated that more than 10 papillary cannulation attempts, MPD cannulation or opacification, suspected sphincter of Oddi dysfunction, and precut methods were significant risk factors independently associated with PEP. Limitations Lack of randomization. Conclusions For selective cannulation of the CBD, the risk of inducing PEP is similar with the ConI and GW techniques in high-risk and low-risk patients. Any manipulation of the MPD must be considered a high-risk factor for PEP, such as multiple attempts on the papilla or use of the precut method.