Background: Several studies have reported the cost-effectiveness of sodium-glucose co-transporter 2 inhibitors in heart failure patients; however, their economic implications have not been sufficiently elucidated in Japan., Methods: A Markov cohort model was developed to evaluate the cost-effectiveness of empagliflozin plus standard of care (SoC) vs. SoC for patients with heart failure with reduced ejection fraction (HFrEF) in Japan. Model inputs, including risk of clinical events, costs, and utilities based on Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores were derived from EMPEROR-Reduced trial data, published literature, and a claims database., Results: The model predicted lower lifetime hospitalizations for heart failure (HHFs) and additional quality-adjusted life-years (QALYs; 0.21) for empagliflozin plus SoC vs. SoC in the overall population. Increased costs of ¥100,495/patient ($772/patient), primarily driven by higher drug costs of ¥239,558/patient ($1,840/patient), were largely offset by reduced HHF management costs of -¥166,160/patient (-$1,276/patient), yielding an incremental cost-effectiveness ratio (ICER) of ¥469,672/QALY ($3,608/QALY). Results were consistent among subgroups and sensitivity analyses. In probabilistic sensitivity analysis, 82.5 % of runs were below the Japanese ICER reference value of ¥5,000,000/QALY ($38,408/QALY)., Conclusions: Empagliflozin was demonstrated to be cost-effective for HFrEF patients in Japan based on the EMPEROR-Reduced trial data., Competing Interests: Declaration of competing interest Hiroyuki Tsutsui received remuneration for attending meetings from Kowa Company, Limited, TEIJIN PHARMA, Nippon Boehringer Ingelheim Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Pfizer Japan Inc., Ono Pharmaceutical CO., LTD, Daiichi Sankyo Company, Novartis Pharma K.K, Bayer Yakuhin, Ltd., Otsuka Pharmaceutical, AstraZeneca K.K, received manuscript fee from Nippon Rinsho, received research funding from Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co., Ltd., IQVIA Services Japan K.K, medinet,inc, Medical Innovation Kyushu, Co., Ltd., Kowa Company, Daiichi Sankyo Company, Johnson & Johnson, NEC Corporation, received scholarship funds from Nippon Boehringer Ingelheim Co., Ltd., St.Mary's Hospital, TEIJIN PHARMA, Daiichi Sankyo Company, Mitsubishi Tanabe Pharma Corporation. Hiroyuki, Sakamaki received research funding from TOWA PHARMACEUTICAL CO., LTD. Shin-ichi Momomura received remuneration for attending meeting from Nippon Boehringer Ingelheim Co., Ltd. Yasushi Sakata received remuneration for attending meeting from Otsuka Pharmaceutical, Daiichi Sankyo Company, Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co., Ltd., AstraZeneca K.K, Ono Pharmaceutical, CO., LTD, Novartis Pharma K.K, received research funding from Nippon Boehringer Ingelheim, received scholarship funds from Ono Pharmaceutical, CO., LTD, Otsuka Pharmaceutical, Daiichi Sankyo Company, Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co., Ltd. Yutaro Kotobuki and Daisuke Nitta are employees of Nippon Boehringer Ingelheim Co., Ltd., while Stephan Linden is employed by Boehringer Ingelheim International GmbH. Tatsunori Murata is an employee of CRECON Medical Assessment Inc. Tetsuaki Hirase is an employee of Eli Lilly Japan K. K. and has stock from Eli Lilly and Company. Odette Reifsnider, Pal Rakonczai, and Matthew Stargardter are employees of Evidera, a biopharmaceutical research and consulting firm. In these salaried positions, they work with a variety of companies and are explicitly precluded from accepting any payment or honoraria directly from those companies for services rendered. Evidera received payment from Nippon Boehringer Ingelheim Co., Ltd. for collaboration on this project and article., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)