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Periprosthetic joint infection (PJI) following total knee arthroplasty is a growing concern, as the demand for total knee arthroplasty (TKA) expands annually. Although 2-stage revision is considered the gold standard in management, there is substantial morbidity and mortality associated with this strategy. One-stage revision is associated with lower mortality rates and better quality of life, and there has been increased interest in utilizing the 1-stage strategy. However, surgeons are faced with a difficult decision regarding which strategy to use to treat these infections, considering uncertainty with respect to eradication of infection, quality of life, and societal costs with each strategy. The purpose of the current study was to use decision analysis to determine the optimal decision for the management of PJI following TKA.An expected-value decision tree was constructed to estimate the quality-adjusted life-years (QALYs) and costs associated with 1-stage and 2-stage revision. Two decision trees were created: Decision Tree 1 was constructed for all pathogens, and Decision Tree 2 was constructed solely for difficult-to-treat infections, including methicillin-resistant infections. Values for parameters in the decision model, such as mortality rate, reinfection rate, and need for additional surgeries, were derived from the literature. Medical costs were derived from Medicare data. Sensitivity analysis determined which parameters in the decision model had the most influence on the optimal strategy.In both decision trees, the 1-stage strategy produced greater health utility while also being more cost-effective. In the Monte Carlo simulation for Decision Trees 1 and 2, 1-stage was the dominant strategy in about 85% and 69% of the trials, respectively. Sensitivity analysis showed that the reinfection and 1-year mortality rates were the most sensitive parameters influencing the optimal decision.Despite 2-stage revision being considered the current gold standard for infection eradication in patients with PJI following TKA, the optimal decision that produced the highest quality of life was 1-stage revision. These results should be considered in shared decision-making with patients who experience PJI following TKA.Economic and Decision Analysis Level IV. See Instructions for Authors for a complete description of levels of evidence.