Uncertainties still exist about the clinical benefit of pharmacological prevention of post-ERCP pancreatitis by either antisecretory drugs such as somatostatin and its long-acting analogue octreotide, or protease inhibitors such as gabexate mesilate. Recent, large-scale prospective studies have reported a fourfold reduction in acute pancreatitis as compared to a placebo with the prophylactic administration of either gabexate mesilate or somatostatin, whereas octreotide was found to be ineffective. An initial meta-analysis of all available controlled trials on this topic has confirmed these findings. The indiscriminate use of these drugs in all patients is unlikely to be cost-effective, but the selective use of prophylaxis for high-risk patients might be advocated. Moreover, inasmuch as 85% of complications developed within 4 to 6 hours of completing the ERCP, it would be reasonable to infuse drugs only for this limited length of time. A recent prospective trial, carried out on high-risk patients, has surprisingly documented a higher incidence, although a non-significant one, of pancreatitis in patients who received short-term prophylaxis with somatostatin or gabexate mesilate than those given a placebo: 11.5% and 8.1% vs. 6.5%, respectively. In order to explore this discrepancy, the original meta-analysis was updated by including data of this negative trial: heterogeneity among the trials was apparent. A careful scrutiny of the most recent studies has revealed differences in patient population, protocols of drug administration, technique and operator-related risk factors for complications among the trials, which could explain, by themselves, the contrasting results reported by the interventional studies. In conclusion, current literature does not support the prophylactic use of either somatostatin or gabexate mesilate for the prevention of ERCP-related pancreatic damage, even in patients deemed to be at high risk for complications. At present, post-ERCP complications (and pancreatitis) can be prevented efficaciously by appropriate selection of patients, mastering of the technique and operator competence.