Prosthetic joint infection (PJI) is a costly and potentially fatal complication in total ankle arthroplasty (TAA). Some surgeons apply topical vancomycin powder to minimize the risk of infection during TAA procedures. The purpose of our study was to determine the cost-effectiveness of using vancomycin powder to prevent PJI following TAA and to propose an economic model that can be applied by foot and ankle surgeons in their decision to incorporate vancomycin powder in practice. Using our institution’s records of the cost of 1 g of topical vancomycin powder, we performed a break-even analysis and calculated the absolute risk reduction and number needed to treat for varying costs of vancomycin powder, PJI infection rates, and costs of TAA revision. Costing $3.06 per gram at our institution, vancomycin powder was determined to be cost-effective in TAA if the PJI rate of 3% decreased by an absolute risk reduction of 0.02% (Number Needed to Treat = 5304). Furthermore, our results indicate that vancomycin powder can be highly cost-effective across a wide range of costs, PJI infection rates, and varying costs of TAA revision. The use of vancomycin powder remained cost-effective even when (1) the price of vancomycin powder was as low as $2.50 to as high as $100.00, (2) infection rates ranged from .05 to 3%, and (3) the cost of the TAA revision procedure ranged from $1000 to $10 000.Levels of Evidence:IV