INTRODUCTION: Routine antibiotic prophylaxis (AP) to prevent prosthetic joint infection remains controversial. The lack of prophylaxis guideline consensus from the American Academy of Orthopaedic Surgeons (AAOS) and the American Dental Association (ADA) contributes to clinician confusion. OBJECTIVES: This cost-effectiveness decision model informs the AP debate and guideline development by comparing the benefits, harms, and costs of alternative prophylaxis strategies. METHODS: A Markov state-transition model was developed comparing lifetime health outcomes and costs of alternative AP strategies for dental patients aged 65 y with a history of total knee arthroplasty (TKA). Based on our interpretation of AP recommendations from the AAOS and ADA, incremental cost-effectiveness ratios were calculated to compare the following strategies: no AP, AP for the first 2 y after a TKA, and lifetime AP. RESULTS: The no-AP strategy had the lowest average lifetime costs ($17,119) and quality-adjusted life years (11.2151). Compared with a no-prophylaxis strategy, the 2-y AP strategy had incremental costs of $56 and 0.0006 QALYs gained and was cost-effective (incremental cost-effectiveness ratio = $95,100) when a willingness-to-pay threshold of $100,000 per quality-adjusted life year was used. Based on the results of 1-way sensitivity analysis, the no-AP strategy was cost-effective when we modestly increased base case amoxicillin adverse event estimates that were substantially lower than estimates reported in previous models. When plausible combinations of important model parameters were varied, model results suggested that there may be clinical scenarios when AP may be appropriate for some medically at-risk patient populations. CONCLUSION: The results of cost-effectiveness decision modeling generally support questioning routine AP for dental patients with TKA. Sensitivity analyses suggest that prophylaxis may be cost-effective for patient populations with a higher medical risk of infection. This finding is consistent with the recommendations of the 2015 ADA practice guideline and the appropriate use criteria jointly developed by the AAOS and the ADA. KNOWLEDGE TRANSFER STATEMENT: The results of this decision modeling research support the contention that routine AP before invasive dental procedures to prevent prosthetic joint infection may not be cost-effective for patients without medical conditions, potentially conferring a higher infection risk. Model sensitivity analyses suggest that there may be clinical situations when medically at-risk patients benefit from AP.