Background and Purpose—The aim of this study was to determine the effectiveness of pioglitazone compared with placebo for improving insulin sensitivity among nondiabetic patients with a recent transient ischemic attack (TIA) or nondisabling ischemic stroke and impaired insulin sensitivity.Methods—Eligible subjects were men and women >45 years of age who had no history of diabetes, fasting glucose <7.0 mmol/L, and impaired insulin sensitivity according to an index calculated from insulin and glucose blood levels obtained during an oral glucose tolerance test. Eligible subjects were randomized to pioglitazone 45 mg/d or placebo. After 3 months of therapy, the glucose tolerance test was repeated.Results—Between July 2000 and June 2001, we performed oral glucose tolerance tests on 75 patients with no history of diabetes, among whom 36 (50%) were found to have impaired insulin sensitivity and fasting glucose <7.0 mmol/L. Among these 36, 20 consented to the trial. Patients assigned to pioglitazone (n=10) and placebo (n=10) were similar in insulin sensitivity, age, obesity, and index event (stroke compared with TIA), but patients assigned to pioglitazone were less likely to be male (4 compared with 9). The mean proportional increase in insulin sensitivity was 62% among patients assigned to pioglitazone compared with a −1% decline among patients assigned to placebo (P=0.0006). Mean C-reactive protein concentration declined from 0.30 to 0.20 mg/L among patients assigned to pioglitazone and increased from 0.41 to 0.45 mg/L among patients assigned to placebo (P=0.06 for comparison of mean change).Conclusions—Pioglitazone is effective for improving insulin sensitivity among patients with recent TIA or stroke and impaired insulin sensitivity.