Background: Previous studies demonstrated that objective response by modified Response Evaluation Criteria In Solid Tumors (mRECIST) is an independent predictor of overall survival (OS) in patients with hepatocellular carcinoma (HCC). The European Association for the Study of the Liver indicates additional studies are needed to further validate the predictive value of tumor response. In this post hoc retrospective analysis, we investigated the association between objective response by investigator-assessed mRECIST and OS for patients from the REFLECT trial, a randomized, open-label, non-inferiority phase 3 trial of lenvatinib versus sorafenib in first-line treatment of patients with unresectable HCC. Methods: We evaluated the association between objective response per investigator-assessed mRECIST and OS for the overall REFLECT population. We also conducted landmark analyses of OS by objective response status at 2, 4, and 6 months after randomization. Findings: Median OS was 22·4 months (95% CI: 19·7–26·0) for responders compared with 11·4 months (95% CI: 10·3–12·3) for nonresponders (hazard ratio [HR]: 0·61; 95% CI: 0·49–0·76; p <0·001). OS was significantly prolonged for responders compared with nonresponders at the 2-month (HR: 0·61; 95% CI: 0·49–0·76; p <0·001), 4-month (HR: 0·63; 95% CI: 0·51–0·80; p <0·001), and 6-month landmarks (HR: 0·68; 95% CI: 0·54–0·86; p =0·001). An exploratory multivariate Cox regression analysis identified objective response by mRECIST as an independent predictor of OS in patients with HCC, regardless of treatment (HR: 0·611; 95% CI: 0·490–0·762; p <0·0001). Interpretation: Objective response by mRECIST was an independent predictor of OS in patients with HCC, regardless of treatment. Patients achieving a complete or partial response by mRECIST had significantly longer survival compared with patients with stable, progressive, or nonevaluable disease. Trial Registration: ClinicalTrials.Gov Identifier for the source study: NCT01761266 Funding Statement: This study was funded by Eisai Inc., Woodcliff Lake, NJ, USA, and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA Declaration of Interests: Masatoshi Kudo: Reports honoraria and consulting or advisory fees from Bayer AG, and Eisai Co., Ltd.; honoraria from Bayer AG, Bristol-Myers Squibb, EA Pharma Co., Ltd., Eisai Co., Ltd., and Merck Sharp & Dohme; and research funding from Bayer AG, Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co., Ltd., Merck Sharp & Dohme, Otsuka Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., and Taiho Pharmaceutical. Richard S. Finn: Reports consulting or advisory fees and research funding from Bayer AG, Bristol-Myers Squibb, Eisai Co., Ltd., Eli Lilly and Company, Merck Group, Novartis International AG, and Pfizer Inc; and consulting or advisory fees from AstraZeneca plc. Shukui Qin: Declares no competing interests. Kwang-Hyub Han: Reports research funding and consulting or advisory fees from Eisai Co., Ltd. and KOWA Company, Ltd.; and consulting or advisory fees from Bayer AG. Kenji Ikeda: Reports honoraria from Eisai Co., Ltd. and Sumitomo Dainippon Pharma Co., Ltd. Ann-Lii Cheng: Reports consulting or advisory fees from Bristol-Myers Squibb, Ono Pharmaceutical Co., Ltd., Novartis International AG, Bayer AG, Merck Group, and Merck Sharp & Dohme. Francesco Tovoli: Reports consulting or advisory fees from Bayer AG. Kazuomi Ueshima: Reports honoraria and consulting or advisory fees from Bayer AG and Eisai Co., Ltd. Hiroshi Aikata: Declares no competing interests. Arndt Vogel: Reports consulting or advisory fees from Novartis International, Delcath Systems, Eli Lilly and Company, Roche Holding AG, Amgen Inc., Bayer AG, and Baxalta; honoraria from Novartis International, Roche Holding AG, Bayer AG, Sanofi S.A., Amgen Inc., Delcath Systems, Eli Lilly and Company, Bristol-Myers Squibb, and Merck Sharp & Dohme; personal fees from Bayer AG, Roche Holding AG, and Ipsen Corporate; and research funding from Novartis International. Carlos Lopez Lopez: Reports consulting or advisory fees and research funding from BristolMyers Squibb, Merck Sharp and Dome, Eisai Co., Ltd., Merck Group, Servier, Sanofi S.A., Roche/Genentech, EXELISIS, Daichii-Sankyo, Ipsen, and AstraZeneca; and consulting or advisory fees from Bayer AG, Amgen Inc., Novartis, and Pfizer Inc. Marc Pracht: Declares no competing interests. Zhiqiang Meng: Declares no competing interests. Bruno Daniele: Reports honoraria from Bristol-Myers Squibb and Bayer AG; consulting or advisory fees from Bayer AG, Eisai Co., Ltd., Eli Lilly and Company, Ipsen Corporate, and Merck Sharp & Dohme; and personal fees from Amgen Inc., Bayer AG, Bristol-Myers Squibb, Celgene Corporation, and Sanofi S.A. Joong-Won Park: Declares no competing interests. Daniel Palmer: Declares no competing interests. Corina E. Dutcus and Kenichi Saito: Employees of Eisai Inc. Toshiyuki Tamai: Employees of Eisai Co., Ltd. Riccardo Lencioni: Reports advisory fees from Eisai Co., Ltd. Ethics Approval Statement: All patients provided written informed consent. The study protocol, protocol amendments, and informed consent forms were reviewed and approved by the relevant institutional review boards and independent ethics committees.