Objective To investigate the impact of hepatitis B virus (HBV) infection on the prognosis of intrahepatic cholangiocarcinoma (ICC). Methods The data of 162 patients with ICC histologically proven by surgery or biopsy in Anting branch of our hospital from Oct. 2015 to Dec. 2019 were retrospectively analyzed. The general information and prognosis of patients with HBV-related ICC (55 cases) and non-HBV-related ICC (107 cases) were compared. Cox proportional hazard regression model was used to analyze the independent factors affecting the prognosis of ICC patients. Results The median survival time of patients in HBV-related ICC group and non-HBV-related ICC group were 26 and 28 months, and the 1-, 3- and 5-year overall survival rates were 80.0%, 29.8%, 14.5% and 79.3%, 31.2%, 16.6%, and the 1-, 3- and 5-year progression-free survival rates were 59.0%, 21.5%, 14.3% and 52.6%, 20.9%, 13.1%, respectively. There were no significant differences in overall survival rate or progression-free survival rate between the 2 groups (P=0.487, 0.634). Stratified analysis by HBV-DNA levels showed no significant difference in overall survival rate or progression-free survival rate between patients with HBV-related ICC in the HBV-DNA≤50 IU/mL group and HBV-DNA>50 IU/mL group (P=0.643, 0.535). Multivariate Cox proportional hazards regression analysis showed that TNM stage Ⅳ (hazard ratio [HR]=3.12, 95% confidence interval [CI] 1.57-6.20, P=0.001), radical surgery (HR=0.47, 95% CI 0.26-0.87, P=0.016) and lymph node metastasis (HR=2.10, 95% CI 1.31-3.36, P=0.002) were the independent influencing factors of overall survival in ICC patients. Conclusion HBV infection has no significant effect on the prognosis of ICC patients. Radical surgery is an independent protective factor for overall survival of ICC patients, and TNM stage Ⅳ and lymph node metastasis are the independent risk factors.