Abstract BACKGROUND Among patients with type 2 diabetes and a history of strokes or transient ischemic attacks, pioglitazone significantly reduces the risk of recurrent stroke. The Insulin Resistance Intervention in Stroke (IRIS) trial found that pioglitazone also reduced the risks of stroke or transient ischemic attacks and new-onset diabetes among patients with insulin resistance. As reported by our previous work, the low-dose pioglitazone was found to provide most of the clinical benefit of high-dose pioglitazone, with fewer adverse effects. We report a model-based economic evaluation to determine the cost-effectiveness of the low-dose pioglitazone versus placebo. METHODS A lifetime Markov model, with an annual cycle length and five health states (event-free, myocardial infarction, stroke, new-onset diabetes, death), was developed. Transition probabilities were extracted from a subgroup of IRIS patients with insulin resistance, defined by a glycosylated hemoglobin level of 5.7% to 6.4% (mean follow-up of 5 years). Health state costs and utilities were based on public sources and literature data, respectively. Utilities were weighted by time spent in health states to calculate quality-adjusted life years (QALYs). The incremental cost per QALY gained was estimated for the population. Annual discount rates of 0%, 1.5%, and 3% were applied. In addition to deterministic analyses, probabilistic sensitivity analyses were conducted to deal with parameter uncertainty. The analyses were conducted from a Canadian public payer perspective in 2023 Canadian dollars. RESULTS The base case results indicated that over a lifetime, the expected costs were CAN$31,534 for low-dose pioglitazone and CAN$55,076 for placebo, resulting in a cost saving of CAN$23,542 in favor of the low-dose pioglitazone. Expected QALYs were 25.10 for the low-dose pioglitazone daily and 19.32 for placebo, resulting in a difference of 5.78 QALYs in favor of low-dose pioglitazone. Probability sensitivity analyses with varying discount rates confirmed these results. CONCLUSIONS Compared with placebo, low-dose pioglitazone is the dominant strategy. Key Points Question Compared with a placebo, is low-dose pioglitazone cost-effective in treating stroke/ transient ischemic attack (TIA) and new-onset diabetes in a simulated population with prediabetics? Findings Over a lifetime, the expected costs were CAN$31,534 for low-dose pioglitazone and CAN$55,076 for placebo, resulting in a cost saving of CAN$23,542 in favor of low-dose pioglitazone. Expected QALYs were 25.10 for low-dose pioglitazone daily and 19.32 for placebo, resulting in a difference of 5.78 QALYs in favor of low-dose pioglitazone. Sensitivity and scenario analyses confirmed the results. Meaning The model-based economic evaluation indicates that low-dose pioglitazone, compared with placebo, is the dominant strategy.