Inflammation is pivotal in atherogenesis. High-sensitivity C-reactive protein (hs-CRP), the prototypic marker of inflammation, has been shown to predict cardiovascular events. Colesevelam hydrochloride (HCl) (WelChol, Sankyo Pharma Incorporated, Parsippany, New Jersey), a specifically engineered bile acid sequestrant, has been shown to be effective in lowering low-density lipoprotein (LDL) cholesterol levels in monotherapy and in combination with statins or fenofibrate. Previously, we have shown that statins lower hs-CRP levels; however, a paucity of data is available examining the effect of colesevelam HCl on hs-CRP levels. The aim of this study was to examine the effect of colesevelam HCl therapy (3.75 g/day for 6 weeks) on hs-CRP in patients with mild hypercholesterolemia in a randomized, double-blind, placebo-controlled study. Twenty-five subjects on colesevelam HCl and 23 subjects on placebo completed the study. The median baseline hs-CRP levels for the treatment and placebo groups are 3.4 and 3.1 mg/L, respectively. Colesevelam HCl therapy resulted in a significant reduction in LDL cholesterol levels (p < 0.001). No significant changes were found in total triglyceride or high-density lipoprotein cholesterol levels between the 2 groups. Furthermore, colesevelam HCl therapy resulted in a significant reduction in hs-CRP levels compared with baseline and placebo (15.9% and 18.7% median reduction, respectively, p < 0.025). No correlation was found between LDL cholesterol lowering and hs-CRP lowering (r = 0.3). In conclusion, our results show that colesevelam HCl monotherapy significantly lowered hs-CRP levels in a double-blind, placebo-controlled study.