Tirzepatide is a novel once-a-week dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist that is used as an addition to diet and exercise to improve blood glucose in adults with type 2 diabetes. It is the first dual glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptor agonist that has been approved by the US Food and Drug Administration. The SURPASS-2 clinical trial demonstrated superiority of tirzepatide 10 mg and 15 mg over semaglutide 1 mg in glycated hemoglobin A1c reduction and weight loss from baseline to week 40. Economic analyses to support coverage and access decision-making for tirzepatide are limited.To evaluate the cost-effectiveness of tirzepatide 10 mg vs semaglutide 1 mg injection over 52 weeks of treatment regarding A1c reduction and weight loss from the perspective of the US health care payer.A decision tree model over a 52-week time horizon was developed to identify incremental treatment-related costs of once-weekly tirzepatide 10 mg vs semaglutide 1 mg injection. Costs were divided by mean reduction in A1c and change in body weight from baseline to week 52 observed in the SURPASS-2 clinical trial. In addition to efficacy, probabilities of adverse events, discontinuation, and need for rescue therapy were derived from the SURPASS-2 study. Drug costs in 2022 US dollars were based on wholesale acquisition cost. Costs associated with adverse events were sourced from the published literature. One-way sensitivity analyses were conducted.Treatment with once-weekly tirzepatide 10 mg injection was associated with a higher cost and larger reduction in A1c and body weight after 52 weeks, compared with once-weekly semaglutide 1 mg injection. The incremental cost-effectiveness ratio for tirzepatide vs semaglutide was $2,247 per 1% reduction in A1c and $237 per 1 kg weight loss. One-way sensitivity analysis suggested that incremental cost-effectiveness ratios were most sensitive to the drug costs and treatment effect on A1c and weight.Once-weekly tirzepatide 10 mg was associated with higher cost and greater reduction in A1c and weight vs semaglutide. Tirzepatide 10 mg is cost-effective compared with semaglutide 1 mg if payers' willingness-to-pay threshold exceeds $2,247 for 1% reduction in A1c level and $237 for 1 kg weight loss.