Introduction: Because the frequency of bile duct invasion in hepatocellular carcinoma (HCC) patients is very rare, there is limited clinical evidence to demonstrate the outcomes of systemic therapy in HCC with bile duct invasion. Objective: Our aim was to clarify the efficacy and safety of sorafenib treatment in patients with unresectable advanced HCC with bile duct invasion. Methods: One hundred and seventy-five patients with advanced HCC were enrolled in this study. We retrospectively compared the outcomes of sorafenib between patients without bile duct invasion [B (−) group, n = 165] and those with bile duct invasion [B (+) group, n = 10]. Results: There were no significant differences in the confirmed objective response rate (ORR) and the confirmed disease control (DC) rate between the B (−) and the B (+) groups (13.9 vs. 20.0%, p = 0.637 for ORR; 47.2 vs. 70.0%, p = 0.202 for DC rate, respectively). There were no significant differences in median overall survival (OS) and time to progression (TTP) between the B (−) group and the B (+) group (14.8 vs. 14.1 months, p = 0.780 for OS; 3.4 vs. 5.7 months, p = 0.277 for TTP, respectively). Post-treatment factors associated with good OS were changes in albumin-bilirubin score (0–6 weeks) of <0.25, and antitumor response at 6 weeks of DC. Though 5 of 10 patients (50%) in the B (+) group had bile duct complications, such as obstructive jaundice and biliary bleeding, these 5 patients were able to recover from biliary troubles by careful and vigorous management with biliary endoscopic intervention, and were able to continue sorafenib therapy safely. Conclusions: Our present results suggest that sorafenib might have potential therapeutic efficacy and safety in advanced HCC patients with bile duct invasion. In case of biliary tract troubles before and during sorafenib treatment, early biliary management may be important to continue sorafenib therapy safely. Further studies are needed to confirm the outcomes of sorafenib in advanced HCC patients with bile duct invasion.