BackgroundThe use of exclusive guide-wire cannulation (e-GW) instead of contrast injection reduces post-ERCP pancreatitis (PEP) and pre-cutting and increases cannulation rate. Herein, we intend to compare e-GW with the hybrid technique (GW-C and/or contrast injection). MethodsProspective single-center randomized comparative study, which included all patients referred to ERCP to our unit. Patients with non-naïve papilla; previous ERCP; direct infundibulotomy, ampullectomy, Billroth II gastrectomy or pancreatic sphincterotomy and patients lost to follow up were excluded. Results727 consecutive patients were assessed. Of these, 588 naïve papilla patients were included and randomized to receive e-GW (n = 299) or GW-C (n = 289) for selective biliary cannulation. The mean age was 60.3 years and 60.5% were women. PEP occurred in 15(5%) cases in e-GW group and 9(3.1%) in the GW-C group (p = 0.29). Time to reach deep cannulation was faster in the latter group (75% < 5 min vs. 50.2% < 5 min, p<0.001). > 10 min until cannulation was observed in 21% vs. 10% of the ERCPs (groups e-GW and GW-C, respectively, p < 0.001). Total ERCP time was also shorter in the GW-C group (12 vs. 10 min; p < 0.001). Pre-cut (23.8 vs.11.8%, p < 0.001) and pancreatic sphincterotomy as a pre-cut technique (15.8 vs. 5.6%, p < 0.001) were used more frequently in the e-GW group. ConclusionsCompared to exclusive G-W- assisted biliary cannulation, the hybrid technique did not significantly reduce the PEP rate, however it promoted faster cannulation and, consequently, reduced the total procedure time and the use of pre-cut techniques.