OBJECTIVES:  To evaluate the pharmacy budget impact of switching severely insulin-resistant patients with type 2 diabetes (T2D) requiring >200 units of daily insulin on basal-bolus regimens or human regular U-500 insulin (U-500R) 20-ml vials to U-500R 3-mL pens from the United States (US) commercial payer and Medicare perspectives. METHODS:  A budget impact model was used to compare pharmacy costs with and without the U-500R pen over a 3-year period. A hypothetical US commercial plan and a Medicare cohort were evaluated separately. T2D prevalence/incidence rates and historical treatment data were used to estimate the number of U-500R–eligible patients. Market share and product substitution rates were projected based on estimates from IMS Lifelink^{TMRESULTS:  :  :  For the US commercial cohort (1,000,000 members), introduction of U-500R pens yielded estimated total cost savings of $324,120 with incremental cost savings per treated member per month (PTMPM) of $24.20 and per member per month (PMPM) of $0.009. For the Medicare cohort, the estimated cost savings were $24,970,603 (total), $22.63 (PTMPM), and $0.018 (PMPM). Although the results were sensitive to U-500R TDD relative to comparators, cost-sharing composition, and rates of uptake from U-500R vials and from comparators, sensitivity analyses showed cost savings with the U-500R pens in most cases for both cohorts. CONCLUSIONS:  :  Incremental switching of high-dose insulin-treated patients with T2D to U-500R pens was estimated to reduce costs from US commercial payer and Medicare perspectives, resulting in pharmacy budget benefits across a wide range of market factors, TDD requirements, and cost-sharing schemes of insurance plans.}