Although colesevelam hydrochloride (HCl) is indicated to reduce low-density lipoprotein cholesterol (LDL-C) in patients with hyperlipidemia and improve glycemic control in patients with type 2 diabetes, its effects on glucose and lipids in patients with prediabetes have not been previously studied. To evaluate the effects of colesevelam HCl in patients with prediabetes, a post-hoc analysis was conducted on data from a 24-week lipid-lowering study. Using baseline laboratory safety data for fasting plasma glucose (FPG), 88 patients were identified as having prediabetes according to American Diabetes Association criteria. Fasting plasma glucose was reduced by 4.0 mg/dL with colesevelam HCl 3.8 g/day and by 6.1 mg/dL with colesevelam HCl 4.5 g/day compared with placebo. Additionally, LDL-C was reduced by 13.2% and 12.0% with colesevelam HCl 3.8 and 4.5 g/day, respectively, versus placebo. Colesevelam HCl 3.8 g/day also significantly reduced total cholesterol and apolipoprotein (apo)B levels, whereas no significant difference in high-density lipoprotein cholesterol, apoA-I, or triglyceride levels was observed versus placebo. In patients with hyperlipidemia and prediabetes, colesevelam HCl improved glycemic control and the lipid profile.