Objective:To determine that early needle-knife sphincterotomy does not increase post-ERCP pancreatitis in patients with difficult biliary cannulation as compared to standard cannulation.Method:This prospective single-centre cohort study was carried out at Pak Emirates Military Hospital from January 2021 to June 2021. Patients requiring ERCP were enrolled in the study (according to inclusion and exclusion criteria) and were subsequently allotted different groups according to the technique used for deep biliary cannulation. Qualitative data was analysed using frequencies and chi square statistics whereas, quantitative data was analysed using mean±SD and one way ANOVA test.Result:The cohort included 114 patients with 52.6% male patients and predominance of relatively younger age group (31-45 years). The most common indication for ERCP was choledocholithiasis (36%) with an overall technical success rate of 96%. Deep cannulation was achieved either through standard cannulation (56%), double guidewire and/or pancreatic stent assisted (10.5%), use of early Needle-Knife Sphincterotomy (19%), NKS as a last resort (3.5%) or Transpancreatic Stenting and/or combined sphincterotomy (6%). Pancreatitis as a complication occurred in 4(3.5%) patients, bleeding in 2(1.8%), on-table desaturation in 2(1.8%) and perforation in 1(0.9%) patient. The occurrence of pancreatitis was only related significantly to inadvertent PD cannulation through univariate and logistic regression analysis whereas, multiple cannulations (>5), gender, age, classification of papilla and the use of early NKS had no impact on pancreatitis or the occurrence of other complications.Conclusion:NKS is an effective and safe modality for deep biliary cannulation and achieving technical success where cannulation is deemed difficult and does not increase the risk of PEP if done by experienced endoscopists in high volume centres.