Reportedly, patients with type 2 diabetes at a high risk for cardiovascular events receiving empagliflozin, compared with placebo, have a lower rate of the primary composite cardiovascular outcome and death from any cause. This study compares the effect of empagliflozin and glimepiride on the endothelial function in patients with type 2 diabetes by flow-mediated dilation (FMD). This prospective, randomized, parallel-group comparison study enrolled 31 patients who were continuously treated with metformin and glargine before bedtime for 12 weeks, followed by the random addition of 10-mg empagliflozin (empagliflozin group, n = 13) or 0.5-mg glimepiride (glimepiride group, n = 18) for 12 weeks. FMD was assessed before and after additional treatment. The primary outcome was a change in FMD (δFMD) with additional treatment before and after 12 weeks. The key secondary outcomes were changes in HbA1c, GA, FPG, body weight, LDL-C, and systolic and diastolic blood pressures. No significant difference existed in age, HbA1c, FMD, and doses of metformin and glargine, and δFMD had no significant difference (empagliflozin, −0.79% ± 1.35%; glimepiride, −0.62% ± 2.78%; P = 0.84). Although HbA1c of both groups improved significantly, the change was not statistically significant. The body weight increased only in the glimepiride group (baseline, 69.6 ± 14.5 kg; 12 weeks later, +1.17 ± 1.99 kg; P = 0.02), but the change was not statistically significant. Likewise, changes in GA, FPG, LDL-C, and systolic and diastolic blood pressures were not significant. In conclusion, empagliflozin besides metformin and glargine did not affect the endothelial function significantly compared with glimepiride in patients with type 2 diabetes. In empagliflozin group, body weight was not changed significantly for 12 weeks. Insulin usage may affect body weight, and that may affect these results. The effect of empagliflozin on endothelial function was not clear in this study. Disclosure H. Tamura: None. Y. Kondo: None. K. Ito: None. S. Satoh: None. Y. Terauchi: Research Support; Self; MSD K.K.. Speaker's Bureau; Self; MSD K.K.. Advisory Panel; Self; MSD K.K.. Research Support; Self; Ono Pharmaceutical Co., Ltd.. Speaker's Bureau; Self; Ono Pharmaceutical Co., Ltd.. Research Support; Self; Novartis Pharma K.K., Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Advisory Panel; Self; Boehringer Ingelheim GmbH. Research Support; Self; Mitsubishi Tanabe Pharma Corporation. Speaker's Bureau; Self; Mitsubishi Tanabe Pharma Corporation. Advisory Panel; Self; Mitsubishi Tanabe Pharma Corporation. Research Support; Self; Daiichi Sankyo Company, Limited. Speaker's Bureau; Self; Daiichi Sankyo Company, Limited. Advisory Panel; Self; Daiichi Sankyo Company, Limited. Research Support; Self; Sanwa Kagaku Kenkyusho Co., Ltd.. Speaker's Bureau; Self; Sanwa Kagaku Kenkyusho Co., Ltd.. Research Support; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Novo Nordisk Inc.. Advisory Panel; Self; Novo Nordisk Inc.. Research Support; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Eli Lilly and Company. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Advisory Panel; Self; Sanofi. Research Support; Self; Sumitomo Dainippon Pharma Co., Ltd.. Speaker's Bureau; Self; Sumitomo Dainippon Pharma Co., Ltd.. Research Support; Self; Shionogi & Co., Ltd.. Speaker's Bureau; Self; Shionogi & Co., Ltd., Bayer Yakuhin, Ltd., Astellas Pharma US, Inc., AstraZeneca. Advisory Panel; Self; AstraZeneca, Teijin Pharma Limited.