This study aimed to compare the safety of the double-guidewire technique (DGT) with that of the conventional single-guidewire technique (SGT) in real-world situations. A total of 240 patients with naïve papilla who underwent endoscopic retrograde cholangiopancreatography (ERCP) at Daegu Catholic University Medical Center between January 2021 and December 2021 were included. The primary outcome was the rate of post-ERCP pancreatitis (PEP) in the SGT and DGT groups. A total of 163 patients (67.9%) belonged to the SGT group, and 77 (32.1%) belonged to the DGT group. The rates of successful biliary cannulation were 95.7% and 83.1% in the SGT and DGT groups, respectively (p=0.002). In the study group, PEP occurred in 14 patients (5.8%). The PEP rates were not significantly different between the SGT and DGT groups (4.3% vs. 9.1%, p=0.150). In the multivariate analysis, the age of <50 years (odds ratio [OR], 9.305; 95% confidence interval [CI], 1.367-63.358; p=0.023) and hyperlipidemia (OR, 7.384; 95% CI, 1.103-49.424; p=0.039) were significant risk factors for PEP in the DGT group. DGT did not increase the PEP rate in patients with naïve papilla. In addition, the age of <50years and hyperlipidemia were significant risk factors for PEP in the DGT group.