Background: Combined hepatocellular intrahepatic cholangiocarcinoma (HCC CC) is a rare tumor defined by pathologic characteristics of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Immunohistochemical (IHC) and genetic profiles (GP) are used for diagnosis and therapeutic decisions, however often mixed tumors are treated as ICC given the presumption this subtype dominates response. Recent studies challenged this practice by demonstrating improved response with immune oncology (IO) therapy. Methods: We identified nine patients with biopsy-proven mixed HCC CC between September 2013 and March 2022. We classified IHC as related to either HCC (HepPar1, Glypican3, CD10, Glutamine Synthetase, CEA, AFP, Arginase1) or ICC (CK19, CK7, CK20, CDX2, Mucicarmine, CA9, MOC31). GP results were classified as HCC-related (TERT, CTNNB1, MYC) or ICC-related (ARID1A, FGFR2, IDH1). Treatment selection, duration of response, and survival were recorded. Results: All subjects had a mix of IHC markers, although six had a preponderance of HCC-related IHC. GP information was available for seven patients, of whom six demonstrated mutations relating only to HCC, and one demonstrated mutations relating only to ICC. All sequenced tumors were MSS, and six of the seven were TMB low. Four subjects used only liver directed therapy for small intrahepatic tumors. Four subjects underwent systemic therapy, a mix of HCC and ICC regimens, three of whom used IO agents. Median survival was 12 months. Conclusions: HCC CC tumor profiling by IHC and GP was more closely aligned with HCC than ICC. However, the median survival for these patients was lower than expected for liver-restricted HCC, more congruent with an ICC phenotype. Although liver-directed therapy was used, the duration of response was shorter than expected for HCC, even in HCC-like tumors. For those receiving systemic therapy, most subjects did not achieve median response with any regimen. Although a previous case series showed good response to IO agents, in our cohort we did not see this effect. In this series, mixed HCC CC was more aggressive than HCC, with largely poor response to both liver directed and systemic therapy. We have insufficient information to correlate systemic treatment response relative to IHC or GP.