INTRODUCTION: This analysis aimed to evaluate the long-term cost-effectiveness of tirzepatide 5 mg versus dulaglutide 0.75 mg (both administered once weekly) in people not achieving glycemic control on metformin, based on the results of the head-to-head SURPASS J-mono trial from a Japanese healthcare payer perspective. METHODS: A cost-utility analysis was performed over a 50-year time horizon using an implementation of the UKPDS Outcomes Model 2 developed in Microsoft Excel. Baseline cohort characteristics, treatment effects and adverse event rates were sourced from the SURPASS J-mono trial. Simulated patients were assumed to receive either tirzepatide 5 mg or dulaglutide 0.75 mg until HbA1c exceeded 8.0%, at which point treatment was discontinued and basal insulin was initiated. Direct costs were derived from the Japan Medical Data Center claims database. Future costs and clinical benefits were discounted at 2% annually. RESULTS: In this cost-utility modeling analysis, tirzepatide 5 mg was associated with lower diabetes-related complication rates, improved life expectancy, improved quality-adjusted life expectancy and higher direct costs versus dulaglutide 0.75 mg. This resulted in an incremental cost-effectiveness ratio (ICER) of JPY (Japanese yen) 1,302,240 per quality-adjusted life year (QALY) gained for tirzepatide 5 mg versus dulaglutide 0.75 mg (JPY 140 = USD 1). Tirzepatide remained cost-effective versus dulaglutide over a range of sensitivity analyses. CONCLUSIONS: In this analysis, tirzepatide 5 mg was associated with an ICER below the commonly quoted willingness-to-pay threshold of JPY 5,000,000 per QALY gained, suggesting that tirzepatide is a cost-effective treatment option for adult patients with type 2 diabetes mellitus, compared with dulaglutide 0.75 mg.