Periprosthetic joint infection (PJI) presents a formidable challenge in the management of megaprostheses, complicating treatment and threatening patient outcomes. With increasing utilization of megaprostheses in orthopedic oncology and complex revision arthroplasty, the incidence of PJI in these prostheses has garnered significant attention. The gold standard for PJI management in megaprostheses remains two-stage revision surgery, offering optimal eradication of infection and functional restoration, but multidisciplinary collaboration between orthopedic surgeons, infectious disease specialists, and microbiologists is imperative for optimizing treatment outcomes. This chapter provides a comprehensive update on the current understanding and management strategies for PJI in megaprostheses, encompassing factors such as patient comorbidities, surgical technique, implant design, and microbial pathogens. Diagnostic modalities, including traditional culture techniques and advanced molecular assays, play a pivotal role in accurately identifying infecting organisms and guiding treatment decisions.