Background and objective: Insulin resistance is thought to be central to the pathogenesis of abdominal obesitylinked metabolic syndrome (MetS). Colestimide, a 2-methylimidazole-epichlorohydrin polymer, is a new bile-acidsequestering resin used to lower LDL cholesterol. In recent reports, bile acid-controlled signaling pathways have shown promise as novel drug targets to treat metabolic disorders, such as obesity, type 2 diabetes, hyperlipidemia, and atherosclerosis. The aim of this study was to evaluate the efficacy of colestimide on weight loss in MetS patients. Methods: Sixty-one patients with MetS who had cardiovascular risk factors were randomized to receive lifestyle counseling with or without colestimide treatment. The primary endpoint was achieved when the reduction in body weight is ≥5%. Additionally, differences in the waist circumference and metabolic-associated profiles between the colestimide group and the control group, which received lifestyle modifications alone, were analyzed. Results: The numbers of participants who achieved ≥5% weight loss significantly favored the colestimide group over the non-colestimide group (71.4% vs. 33.3%; p < 0.01). The mean reduction in waist circumference during the study period (average 22 weeks) was greater with colestimide than without it (10.1 ± 5.4 vs. 7.1 ± 5.2 cm, p < 0.05). Conclusions: The colestimide treatment together with lifestyle intervention was associated with reduction in body weight and waist circumference over a relatively short term in obese subjects. The combination of colestimide and lifestyle intervention may be useful for weight management in MetS patients with cardiovascular risk factors.