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Total ankle replacement and ankle fusion are costly but clinically effective treatments for ankle arthritis. Prior cost-effectiveness analyses for the management of ankle arthritis have been limited by a lack of consideration of indirect costs and nonoperative management. The purpose of this study was to compare the cost-effectiveness of operative and nonoperative treatments for ankle arthritis with inclusion of direct and indirect costs in the analysis.Markov model analysis was conducted from a health-systems perspective with use of direct costs and from a societal perspective with use of direct and indirect costs. Costs were derived from the 2012 Nationwide Inpatient Sample (NIS) and expressed in 2013 U.S. dollars; effectiveness was expressed in quality-adjusted life years (QALYs). Model transition probabilities were derived from the available literature. The principal outcome measure was the incremental cost-effectiveness ratio (ICER).In the direct-cost analysis for the base case, total ankle replacement was associated with an ICER of $14,500/QALY compared with nonoperative management. When indirect costs were included, total ankle replacement was both more effective and resulted in $5900 and $800 in lifetime cost savings compared with the lifetime costs following nonoperative management and ankle fusion, respectively. At a $100,000/QALY threshold, surgical management of ankle arthritis was preferred for patients younger than ninety-six years and total ankle replacement was increasingly more cost-effective in younger patients. Total ankle replacement, ankle fusion, and nonoperative management were the preferred strategy in 83%, 12%, and 5% of the analyses, respectively; however, our model was sensitive to patient age, the direct costs of total ankle replacement, the failure rate of total ankle replacement, and the probability of arthritis after ankle fusion.Compared with nonoperative treatment for the management of end-stage ankle arthritis, total ankle replacement is preferred over ankle fusion; total ankle replacement is cost-saving when indirect costs are considered and demonstrates increasing cost-effectiveness in younger patients. As indications for and utilization of total ankle replacement increase, continued research is needed to define appropriate subgroups of patients who would likely derive the greatest clinical benefit from that procedure.Economic and decision analysis Level II. See Instructions for Authors for a complete description of levels of evidence.