Objective: To investigate the clinical efficacy of hepatic arterial infusion (HAI) of 5-fluorouracil (5-FU) and cisplatin combined with systemic intravenous chemotherapy of gemcitabine in treatment of advanced intrahepatic cholangiocarcinoma (ICC). Methods: Seventy-nine patients with advanced ICC and measurable lesions were enrolled and designated to study group (39 cases) and control group (40 cases) by use of a random number table. Patients in study group underwent HAI of 5-FU+cisplatin combined with intravenous gemcitabine chemotherapy, and those in control group underwent systemic intravenous chemotherapy of gemcitabine and cisplatin. Patients in either group received two repeated courses of treatment, with one month per course. Results: There was no statistical difference in response rate between study group and control group (38.46% vs. 20.00%, P>0.05), but the benefit rate in study group was significantly higher than that in control group (79.49% vs. 60.00%, P<0.05). The levels of tumor biomarkers were significantly decreased in both groups after treatment compared with their pretreatment levels, but their decreasing amplitudes were significantly greater in study group than those in control group (all P<0.05). The 1- and 2-year survival rates showed no statistical difference between study group and control group (63.16% vs. 39.47%; 55.00% vs. 22.50%, both P>0.05), but the 3-year survival rate in study group was significantly higher than that in control group (23.68% vs. 7.50%, P<0.05). There was no statistical difference in incidence of each toxic and adverse reaction during chemotherapy (all P>0.05). Conclusion: HAI combined with systemic intravenous gemcitabine chemotherapy for advanced intrahepatic cholangiocarcinoma patients can achieve relatively good short-term effects and increased long-term survival.