Background In the setting of finite healthcare resources, developing cost-efficient strategies for periprosthetic joint infection (PJI) diagnosis is paramount. The current levels of knowledge allow for PJI diagnostic recommendations based on scientific evidence but do not consider the benefits, opportunities, costs, and risks of the different diagnostic alternatives. Questions/purposes We determined the best diagnostic strategy for knee and hip PJI in the ambulatory setting for Medicare patients, utilizing benefits, opportunities, costs, and risks evaluation through multicriteria decision analysis (MCDA). Methods The PJI diagnostic definition supported by the Musculoskeletal Infection Society was employed for the MCDA. Using a preclinical model, we evaluated three diagnostic strategies that can be conducted in a Medicare patient seen in the outpatient clinical setting complaining of a painful TKA or THA. Strategies were (1) screening with serum markers (erythrocyte sedimentation rate [ESR]/ C-reactive protein [CRP]) followed by arthrocentesis in positive cases, (2) immediate arthrocentesis, and (3) serum markers requested simultaneously with arthrocentesis. MCDA was conducted through the analytic hierarchy process, comparing the diagnostic strategies in terms of benefits, opportunities, costs, and risks. Results Strategy 1 was the best alternative to diagnose knee PJI among Medicare patients (normalized value: 0.490), followed by Strategy 3 (normalized value: 0.403) and then Strategy 2 (normalized value: 0.106). The same ranking of alternatives was observed for the hip PJI model (normalized value: 0.487, 0.405, and 0.107, respectively). The sensitivity analysis found this sequence to be robust with respect to benefits, opportunities, and risks. However, if during the decisionmaking process, cost savings was given a priority of higher than 54%, the ranking for the preferred diagnostic strategy changed. Conclusions After considering the benefits, opportunities, costs, and risks of the different available alternatives, our preclinical model supports the American Academy of Orthopaedic Surgeons recommendations regarding the use of serum markers (ESR/CRP) before arthrocentesis as the best diagnostic strategy for PJI among Medicare patients. Level of Evidence Level II, economic and decision analysis. See Instructions to Authors for a complete description of levels of evidence.