Omentin is an adipokine expressed in visceral adipose tissue and has beneficial effects on insulin action and cardiovascular system, like adiponectin. Recent evidence indicates a paradoxical relationship between high adiponectin levels and mortality across many clinical conditions including type 2 diabetes (T2D) and cardiovascular diseases (CVDs). In this study, we characterized clinical features of T2D patients with elevated adiponectin levels and examined the association between plasma omentin levels and atherosclerosis in those patients. Subjects were 413 patients with T2D. Fasting plasma omentin levels and total adiponectin levels were measured by ELISA, and the mean intima media thickness (IMT) of the common carotid artery was measured by ultrasonography. The medians of plasma omentin levels, adiponectin levels, and IMT were 573 ng/mL, 6.2 µg/mL, and 0.81 mm, respectively. In patients with higher adiponectin levels above the median (high-ADN), IMT tended to be greater, and omentin levels were higher than those in the low-ADN group. The high-ADN group also had older age, higher systolic BP, lower eGFR, BMI, HOMA-R, and HbA1c than the low-ADN group. Interaction analysis indicated an effect modification by adiponectin levels on the association between omentin levels and IMT. Stratified analysis by adiponectin level revealed that omentin levels were independently and negatively associated with IMT in the high-ADN group (β = -0.170, p = 0.022), but not in the low-ADN group, after adjusting for adiponectin levels and CVD risk factors. On the other hand, adiponectin levels were not significantly associated with IMT in either group. These data indicate that the high-ADN group in T2D has multiple CVD risk factors, in whom omentin is inversely associated with IMT. This study suggests a protective role of omentin, rather than adiponectin, against atherosclerosis in T2D with elevated adiponectin levels and accumulated CVD risk factors. Disclosure M. Hatamori: None. T. Morioka: Research Support; Self; Eli Lilly and Company, Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Sanofi K.K., Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Roche Diagnostics K.K., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. Other Relationship; Self; Ono Pharmaceutical Co., Ltd. M. Senda: None. Y. Kakutani: None. Y. Yamazaki: None. K. Mori: Speaker's Bureau; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd. S. Fukumoto: Research Support; Self; Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Kowa Pharmaceutical Europe Co. Ltd., Mitsubishi Tanabe Pharma Corporation, Taisho Toyama Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; Novo Nordisk Inc., Sanofi K.K. A. Shioi: None. T. Shoji: Research Support; Self; Bayer Yakuhin, Ltd., Chugai Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd. Speaker's Bureau; Self; Kissei Pharmaceutical Co., Ltd., Kowa, Kyowa Hakko Kirin Co., Ltd. M. Emoto: Research Support; Self; Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd. Speaker's Bureau; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Kowa Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Taisho Toyama Pharmaceutical CO., Ltd., Takeda Pharmaceutical Company Limited. M. Inaba: None.