In hepatolithiasis, chronic proliferative cholangitis (CPC), an active and longstanding inflammation of stone-containing bile ducts with enhanced mucin-producing activity, not only affects the progression of the disease, it can also induce biliary carcinogenesis. The present study aimed to examine the effect of the epidermal growth factor receptor (EGFR) monoclonal antibody panitumumab (Pani) on CPC. Following the establishment of CPC rat models, periodic acid Schiff staining was used to observe the positive rate of EGFR expression. The expression levels of EGFR, mucin 5AC (MUC5AC), Ki-67, type I collagen and mammalian target of rapamycin (mTOR), and the activity of β-glucuronidase (β-G), were measured. The rats treated with Pani demonstrated a significantly lower degree of hyperproliferation of the epithelium and submucosal glands of the bile duct and collagen fibers of the bile duct wall, a significantly decreased positive rate of EGFR, reduced phosphorylation of mTOR, decreased expression of EGFR, MUC5AC, Ki-67 and type I collagen, and reduced β-G activity. The therapeutic effects in rats treated with 4 and 6 mg/kg of Pani were more marked than those in rats treated with 2 mg/kg of Pani. Collectively, the data obtained in the present study suggest that the EGFR monoclonal antibody Pani can effectively inhibit the excessive proliferation and stone-forming potential of bile duct mucosa in CPC with a receptor saturation effect. Therefore, Pani offers promise as a treatment for the prevention and control of intra-hepatic choledocholithiasis caused by CPC.