AIM: To investigate the feasibility and effectiveness of c-myc shRNA in inhibiting the hyperplastic behavior and lithogenic potentiality of chronic proliferative cholangitis (CPC), in order to prevent stone recurrence and biliary restenosis. METHODS: An animal model of CPC was established by giving intralumenally 0.5 mL of c-myc shRNA. Then, the effects of c-myc shRNA on hyperplastic behavior and lithogenic potentiality of CPC were evaluated by histological observation, immunohistochemistry, realtime PCR and Western blotting for c-myc, proliferating cell nuclear antigen (PCNA), procollagen Ⅲ, mucin 5AC, enzymatic histochemistry for β-glucuronidase, and biochemistry for hydroxyproline in the diseased bile duct.RESULTS: Treatment with c-myc shRNA efficiently suppressed the hyperplasia of biliary epithelium,submucosal gland, and collagen fiber by inhibiting mRNA and protein expression of c-myc. More importantly, it decreased the lithogenic potentiality of CPC by inhibiting the expression of mucin 5AC and the secretion of endogenous β-glucuronidase. Further investigation indicated that c-myc shRNA-3 had a better inhibitory effect on CPC.CONCLUSION: Treatment with c-myc shRNA-3 can control CPC and reduce the lithogenic potentiality of CPC.