Objective:To investigate the expression differences of erbB1 (EGFR) and erbB2 (HER2) in tissues of hepatolithiasis combined with bile duct carcinoma and its clinical significance. Methods: We collected 94 intrahepatic bile duct carcinoma tissues of patients with hepatolithiasis combined with intrahepatic bile duct carcinoma and 50 liver tissues adjacent to carcinoma samples. EGFR and HER2 were detected by immunohistochemical staining after biopsy. Then, we analyzed the expression differences between carcinoma tissues and tissues adjacent to carcinoma. EGFR molecule targeted therapy was performed in some patients (Erlotinib, 150 mg/d, one course of treatment), and 5-year-disease-free survival rate was analyzed. Results: EGFR positive expression rate of the two groups was 58.5% (55/94) and 26.0% (13/50), respectively, and the difference was statistically significant (P < 0.001); HER2 positive expression rate of the two groups was 33.0% (31/94) and 16.0% (8/50), respectivley, and the difference was statistically significant (P < 0.05). In the bile duct carcinoma group, tumor histologic grading, infiltrating depth and hilus lymph node metastasis of EGFR and HER2 positive patients were obviously higher than those of the negative patients, and the difference was statistically significant (P < 0.05). In patients with cholangiocarcinoma, 5-year disease-free survival rate of EGFR or HER2 positive patients was significantly lower than that of the negative patients (P < 0.05). Further found in the molecular targeted therapy, EGFR positive patients treated with erlotinib could extend survival, and 5-year disease-free survival rate was higher than that of EGFR and HER2 positive patients (81.3% vs. 59.4%), but there was no statistically significant difference (P > 0.05). Conclusion: EGFR and HER2 expression in patients with intrahepatic bile duct stone combined with the occurrence of intrahepatic cholangiocarcinoma may play an important role in the development, and the two high expression are closely related to the degree of malignant tumor and clinical prognosis, and may has a guiding significance in clinical molecular targeted therapy.