We aimed to investigate the radiologic antitumor response at 2 weeks after starting lenvatinib for patients with advanced hepatocellular carcinoma (HCC) in real-world practice. This retrospective study enrolled 40 patients who received lenvatinib. Radiologic antitumor response was evaluated according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST). The objective response rate (ORR) at 2 weeks (2W-response) and best overall response when confirmation of complete response, partial response (PR) and stable disease (SD) required (confirmed-response) were 57.5% and 32.5%, respectively. Based on confirmed-response, the overall survival rate was significantly longer in patients with ORR than in those with SD or progression disease (PD) after 12 months (73.2% and 54.2%, p=0.0358). All 13 patients with ORR on confirmed-response were evaluated as PR at 2 weeks. The alpha fetoprotein (AFP) ratio at 2 weeks was a significant factor associated with PR of 2W-response. The median relative dose intensity from 2 to 6 weeks (2-6W-RDI) was significantly lower than that from 0 to 2 weeks (69.6% vs. 100%, p<0.0001). Stratified by the antitumor response at 6 weeks with considering the image evaluation at 2 weeks, the median 2-6W-RDI was significantly lower in patients with PD than in those with PR or SD (45.2% vs. 72.6%, p=0.0482). The radiologic antitumor response at 2 weeks was favorable. Information on a favorable visible therapeutic response very early after lenvatinib initiation can help patients maintain their motivation on treatment and allow physicians to continue treatment effectively and safely. This article is protected by copyright. All rights reserved.