Background: Biliary leaks have been treated with endoscopic management using different techniques with conflicting results. Furthermore the appropriate rescue therapy for refractory leaks has not been established. We evaluated the clinical effectiveness of initial endotherapy for postcholecystectomy biliary leaks using an homogenous approach (sphincterotomy + placement of a 10-French plastic stent) in a large series of patients as well as the optimal and efficacy of rescue endotherapy for refractory biliary leaks. Methods: This was a multicenter, retrospective study of 178 patients who underwent endoscopic management of postcholecystectomy biliary leaks with a combination of biliary sphincterotomy and the placement of a large-bore (10-French) plastic stent. Data were collected to analyze the clinical outcomes and technical success, efficacy of the rescue endotherapy and the need for surgery, adverse events and prognostic factors for clinical success of endotherapy. Results: Following endotherapy, closure of the leak was accomplished in 162/178 patients (91.0%). The multivariate logistic model showed that the type of leak, namely a high-grade biliary leak, was the only independent prognostic factor associated with treatment failure (OR = 26.78; 95% CI = 6.59-108.83; P < 0.01). The remaining 16 patients were treated with multiple plastic stents (MPSs) with a success rate of 62.5% (10 patients). The use of fewer than 3 plastic stents (P = 0.023) and a high-grade biliary leak (P = 0.034) were shown to be significant predictors of treatment failure with MPSs in refractory bile leaks. The 6 patients in whom the placement of MPSs failed were retreated with a fully cover self-expandable metallic stent (FCSEMS), resulting in closure of the leak in all cases. Conclusions: Endotherapy of biliary leaks with a combination of biliary sphincterotomy and the placement of a large-bore plastic stent is associated with a high rate of success (90%). However in our series there were several failures using MPSs as a strategy for rescue endotherapy suggesting that refractory biliary leaks should be treated with FCSEMS especially in patients with high-grade leaks.