Background ERCP can be associated with serious complications. Difficulty in common bile duct (CBD) cannulation is one of the main risk factors for post-ERCP pancreatitis. The double-guidewire technique (DGT) has been considered a promising alternative approach in difficult cannulation situations. Objective To compare the performance of DGT with the standard cannulation technique (SCT) in patients in whom CBD cannulation is difficult to perform. Design Multicenter randomized, controlled trial. Setting Six tertiary referral centers. Patients A total of 188 patients with difficult CBD cannulation defined by completion of 5 unsuccessful cannulation attempts were enrolled. Interventions Ninety-seven patients were assigned to the DGT group and 91 to the SCT group. Both techniques were compared for an extra 10 cannulation attempts. Main Outcome Measurements CBD cannulation rate, number of attempts required to cannulate, and ERCP-related complications. Results Successful CBD cannulation was achieved in 46 of 97 (47%) patients in the DGT group compared with 51 of 91 (56%) in the SCT group (OR 0.85; 95% CI, 0.64-1.12). The median number of attempts required for each group was 9 and 7, respectively ( P = .128). The incidence of post-ERCP pancreatitis was 17% in the DGT group and 8% in the SCT group (OR 2.13; 95% CI, 0.89-5.05). Limitations Reduced number of enrolled subjects and a lack of detailed information regarding the number and extent of pancreatic duct contrast injections. Conclusions In patients with difficult CBD cannulation, DGT was not superior to SCT in achieving CBD cannulation. DGT might be associated with a higher risk of post-ERCP pancreatitis. (This study has been registered in ClinicalTrials.gov with identifier NCT00270868 .)