Background: Primary liver carcinomas with hepatocellular and cholangiocellular differentiation (b[HB]-PLC) are rare. Surgery offers the best prognosis, but there is a paucity of literature to guide therapy for patients with advanced or unresectable disease. This study aimed to evaluate outcomes of hepatic-directed therapy compared with those of systemic chemotherapy and surgery. Methods: A retrospective evaluation of patients with b(HB)-PLC from 1 January 2008 to 1 September 2014 was conducted. The patients were divided into the following four groups: transplantation (TX) group, surgical resection (SX) group, hepatic directed (HD) group, and systemic chemotherapy alone (SC) group. Overall and progression-free survival, treatment response, and clinicopathologic data were analyzed. Results: The study included 79 patients (37 females) with an average age of 62 years. The number of patients in each group were as follows: TX group (n = 6), SX group (n = 27), HD group (n = 18), and SC group (n = 28). The mean follow-up periods were 33 months for the TX group, 17 months for the SX group, 14 months for the HD group, and 7 months for the SX group. Overall, 28 % of the patients had cirrhosis and 35 % had viral hepatitis. The candidates for surgery comprised 42 % of the patients. The HD group (n = 18) had a significantly greater objective response than the SC group (n = 28) (47 vs. 6 %; p = 0.02). Two patients who underwent hepatic arterial infusion pump treatment were downstaged to resection. A trend toward improved OS/PFS was observed in the HD group versus the SC group, although statistically significant. The SX group had significantly improved survival (p < 0.001) as did the transplanted patients. Conclusions: Although surgery offers the best survival for b(HB)-PLC patients, only a minority are candidates for surgery. Because HD therapy showed a superior objective response over SC therapy, it may offer a survival advantage and may downstage patients for surgical resection or transplantation.