Prosthetic joint infection (PJI) is the most common mode of failure of megaprostheses, yet the literature on the topic is scarce, and studies report conflicting data regarding the optimal treatment strategy. Patients with megaprostheses PJI are often immunosuppressed, and surgeons must balance the trade-off between treatment efficacy and morbidity associated with the surgery aiming for infection eradication. Our review on megaprostheses PJI focuses on two axes: (1) risk factors and preventative strategies; and (2) surgical strategies to manage this condition. Risk factors were classified as either unmodifiable or modifiable. Attempts to decrease the risk of PJI should target the latter group. Strategies to prevent PJI include the use of silver-coated implants, timely discontinuation of perioperative antibiotic prophylaxis, and adequate soft tissue coverage to diminish the amount of dead space. Regarding surgical treatment, main strategies include debridement, antibiotics, implant retention (DAIR), DAIR with modular component exchange, stem retention (DAIR plus), one-stage, and two-stage revision. Two-stage revision is the "gold standard" for PJI in conventional implants; however, its success hinges on adequate soft tissue coverage and willingness of patients to tolerate a spacer for a minimum of 6 weeks. DAIR plus and one-stage revisions may be appropriate for a select group of patients who cannot endure the morbidity of two surgeries. Moreover, whenever DAIR is considered, exchange of the modular components should be performed (DAIR plus). Due to the low volume of megaprostheses implanted, studies assessing PJI should be conducted in a multi-institutional fashion. This would allow for more meaningful comparison of groups, with sufficient statistical power. Level of evidence: IV.