There is yet to be a standardized total knee arthroplasty (TKA) surgical protocol that has been studied to a sufficient degree to offer evidence-based practices regarding infection and readmission prevention. Although high-level evidence is often sought to provide guidance concerning protocol- and process-level decisions, the literature is often confusing and nondefinitive in its conclusions and recommendations regarding periprosthetic joint infection and readmission prevention. Areas of study that require further investigation include the following: the role of patient optimization and preoperative mitigation of risk; perioperative antibiotics; operating room environment; blood management; operative techniques, implants, and infection prevention measures; wound care management; and post acute care. Patient-associated modifiable risk must be optimized to decrease poly joint infection rates after TKA. Protocol measures for TKA need to be standardized, and evidence-based practice measures need to be validated.