Background: The treatment landscape of advanced hepatocellular carcinoma (HCC) has made significant advances with the use of oral multikinase inhibitors and immunotherapy-containing regimens. However, there is minimal data with regards to which biomarkers may predict treatment responses in this population. The increased use of next-generation sequencing (NGS) has identified the most frequent mutations in HCC, including TERT promoter mutations which are found in up to 65% of patients. With the high frequency of these mutations, additional studies are needed to investigate their associations with treatment outcomes. Methods: Our team performed a retrospective study to determine the association between TERT promoter mutations in HCC and responses to first-line systemic therapies. All patients in this study underwent NGS testing on tumor tissue or peripheral blood samples. Responses to treatment were determined by imaging at least 6 weeks after the start of systemic therapy. Results: There were 128 HCC patients included in this study with TERT promoter mutations found in 72 patients (56.3%). All patients received first-line therapy with either an immunotherapy-based regimen or oral multikinase inhibitor monotherapy (lenvatinib or sorafenib). When looking at responses to all first-line therapies, patients with TERT promoter mutations were found to have significantly higher rates of disease progression (PD) compared to those without TERT promoter mutations (34.7% vs 17.9%, p = 0.04). In addition, when stratifying responses by type of systemic therapy, the TERT promoter-mutated population had notably higher rates of PD with immunotherapy regimens compared to patients without TERT mutations (34.6% vs 10.8%, p = 0.01). In contrast, there was no significant difference in rates of PD with oral multikinase inhibitor monotherapy between TERT mutated and TERT non-mutated individuals (35% vs 31.6%, p = 1). See table for further details. Conclusions: In this study, HCC patients with TERT promoter mutations were found to have significantly higher rates of PD to first-line therapies and, specifically, immunotherapy-containing regimens. Given the prevalence of these mutations in the HCC population, further investigation is needed to clarify this association and its impact on patient survival.