About one million knee and hip joint replacements are performed annually in the United States and have been reported to become infected 2.1% and 2.3% of the time. The economic burden of prosthetic joint infection in the United States has been estimated to be annually over $1.5 billion, and the infections are associated with significant morbidity and even mortality. Oral bacteria entering the blood were initially thought to be a possible cause of PJI, leading to the concept of giving the patient prophylactic antibiotics before undergoing invasive, bacteremia-causing dental procedures. This evidence-based QRG reviews the history of recommendations for providing invasive dental procedures for patients with prosthetic joints, presents current literature findings regarding the efficacy of antibiotic pre-medication in preventing prosthetic joint infections, and analyzes the tenets of evidence-based dentistry and its impact on contemporary antibiotic prophylaxis decisions for patients with prosthetic joints. The QRG is a critical reference for the dental clinician assessing a patient with orthopedic implants. It also provides background information for the entire dental office team to answer patients’ questions regarding prophylactic antibiotic therapy.