Technical Abstract: Cholestyramine is a cationic polymer prescribed to lower cholesterol in humans. We investigated the effects of cationic hydroxyethyl cellulose (cHEC) on weight loss and metabolic disorders associated with obesity using both hamster and diet-induced obese mouse models. Golden Syrian hamsters and obese male C57BL/6J mice were supplemented with cHEC in high-fat diets for four and five weeks, respectively. cHEC supplementation in a high-fat diet lead to significant weight gain reduction in hamsters and weight loss in obese mice. In addition, significant decreases in mesenteric adipose, liver weights, concentrations of plasma cholesterol, and hepatic lipids were shown. In mice, at 4% cHEC a significant improvement in glucose homeostasis, insulin sensitivity, leptin and adiponectin concentrations were observed. Expression of CYP7A1, CYP51, LDLR and SCD1 were significantly changed in the liver of supplemented cHEC hamsters. Moreover, increases in fecal secretion of total bile acids, sterols, and fats indicated altered fat absorption when cHEC is supplemented in the diet for mice but not for hamsters.