Background: Hepatocelluar carcinoma (HCC) is one of the fastest growing causes of cancer-related deaths in the US. The objectives of this study were to examine the lines of loco-regional therapies received and the healthcare economic burden of patients newly diagnosed with HCC in the US. Methods: Patients (≥18 years of age) diagnosed with HCC who received ≥1 loco-regional therapy (index date) after diagnosis were identified from the MarketScan Commercial and Medicare Supplemental databases (July 1, 2013-May 31, 2018). Patients were required to have ≥6 months of continuous insurance enrollment before the index date and ≥1 month after (follow-up period). The follow-up period was censored when patients received any systemic therapy. During the follow-up periods, the number of patients who received radiation therapy, ablative therapy, and embolization procedures (transarterial embolization/chemoembolization [TAE] and radioembolization [TARE]) were examined. All-cause and HCC-related healthcare costs (total and patient out-of-pocket [OOP] payments per patient per month [PPPM]) were also measured. Results: Among the 2,101 patients newly diagnosed with HCC who received ≥1 loco-regional therapy, median age was 64 years and 75.0% were male; the mean follow-up duration was 11.5 months. During the follow-up periods, 28.1% (n = 590) received radiation therapy, 27.3% (n = 574) ablative therapy, and 77.3% (n = 1,623) embolization therapy (TAE: 68.7% [n = 1,443]; TARE: 20.7% [n = 434]); 30.9% of patients received multiple loco-regional therapies. During the follow-up periods, total all-cause healthcare costs were a mean of $20,316 (OOP: $378) PPPM, of which 70.7% ($14,359; OOP: $227 PPPM) were HCC-related. The breakdown of healthcare costs is shown in the table. Conclusions: According to the findings of this large-scale real-world analysis of patients newly diagnosed with HCC in the US, a vast majority received at least one embolization procedure. The monthly healthcare economic burden of patients with HCC treated with local-regional therapies is relatively high.