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Aims: Prior cost-effectiveness analyses on osseointegrated prosthesis for transfemoral unilateral amputees have analyzed outcomes in non-USA countries using generic quality of life instruments, which may not be appropriate when evaluating disease-specific quality of life. These prior analyses have also focused only on patients who had failed a socket-based prosthesis. The aim of the current study is to use a disease-specific quality of life instrument, which can more accurately reflect a patient’s quality of life with this condition in order to evaluate cost-effectiveness, examining both treatment-naïve and socket refractory patients. Methods: Lifetime Markov models were developed evaluating active healthy middle-aged male amputees. Costs of the prostheses, associated complications, use/non-use, and annual costs of arthroplasty parts and service for both a socket and osseointegrated (OPRA) prosthesis were included. Effectiveness was evaluated using the questionnaire for persons with a transfemoral amputation (Q-TFA) until death. All costs and Q-TFA were discounted at 3% annually. Sensitivity analyses on those cost variables which affected a change in treatment (OPRA to socket, or socket to OPRA) were evaluated to determine threshold values. Incremental cost-effectiveness ratios (ICERs) were calculated. Results: For treatment-naïve patients, the lifetime ICER for OPRA was $279/quality-adjusted life-year (QALY). For treatment-refractory patients the ICER was $273/QALY. In sensitivity analysis, the variable thresholds that would affect a change in the course of treatment based on cost (from socket to OPRA), included the following for the treatment-naïve group: yearly replacement components for socket > $8,511; cost yearly replacement parts OPRA < $1,758; and for treatment-refractory group: yearly replacement component for socket of > $12,467. Conclusion: The use of the OPRA prosthesis in physically active transfemoral amputees should be considered as a cost-effective alternative in both treatment-naïve and treatment-refractory socket prosthesis patients. Disease-specific quality of life assessments such as Q-TFA are more sensitive when evaluating cost-effectiveness. Cite this article: Bone Jt Open 2024;5(3):218–226.