Background: In the United States (U.S.), lenvatinib monotherapy was approved in August 2018 for first-line treatment of patients with unresectable hepatocellular carcinoma (uHCC) based on the pivotal trial, REFLECT. Real-world data are essential to assess if this efficacy translates into effectiveness in clinical practice. The main objective of our real-world data (RWD) study was to assess clinical characteristics and effectiveness of lenvatinib among patients treated in U.S. clinical practices. Methods: A retrospective patient chart review study was conducted among adult patients (≥18 years) in the U.S. initiating lenvatinib monotherapy as first-line (1L) systemic therapy for uHCC between Aug 2018 and Sept 2019 and with ECOG status of 0 or 1. Data were extracted from individual patients’ electronic health records and captured in electronic case report forms. Clinical outcomes assessed include provider-reported best response, progression-free survival (PFS) and overall survival (OS). PFS and OS were estimated using Kaplan-Meier methods. For PFS, patients were censored at end of treatment or end of follow-up in case of ongoing treatment, while censoring occurred at end of follow-up for OS. Results: Among 233 patients treated with 1L lenvatinib monotherapy, majority were male (68%) and most were Caucasian (52%) or African American (25%). Median age was 63 years and median body weight was 76 kg. The most common etiologies of liver disease were hepatitis C (36%), alcohol-related liver disease (28%), hepatitis B (16%) and non-alcoholic steatohepatitis (14%). Most patients had compensated cirrhosis, with 49% Child Pugh A and 43% Child Pugh B. All patients had uHCC, with most having Barcelona Clinic Liver Cancer stage B (29%) or C (44%) disease. Portal vein invasion was reported in 19%, of whom7% had main portal vein involvement. The median starting dose of lenvatinib was 12 mg daily. Over a median follow-up period of 9 months from HCC diagnosis, median PFS and OS were not reached. At 6 and 12 months landmark PFS was 85% and 65%, respectively and landmark OS was 92% and 73%, respectively. In the overall cohort, provider-reported best response was complete response (CR): 21%, partial response (PR):44% and stable disease (SD): 26%. Based on RECIST 1.1 (n = 125) CR:16%, PR:54%, SD:26% and mRECIST (n = 11) CR:73%, PR:0% and SD:18% were reported. Average duration of lenvatinib treatment was 7.4 months (median: 6.7 months) with 61% of patients remaining on lenvatinib at end of follow-up. Second-line (2L) treatment was initiated in 32 patients, with immunotherapy (50%), sorafenib (31%) and regorafenib (9%) being most common. Median time to 2L treatment from initiation of lenvatinib was about 8 months. Conclusions: Results from this retrospective real-world study in an U.S. population affirm the clinical effectiveness of 1L lenvatinib monotherapy among patients with uHCC.