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Total joint arthroplasty is an important therapeutic option for patients suffering from osteoarthritis and other degenerative joint diseases. However, joint replacements are susceptible to periprosthetic joint infection especially by staphylococci and other gram-positive organisms. Antibiotic prophylaxis, or systemic administration of antibiotics prior to primary arthroplasty, has been shown to reduce rates of surgical site infection and periprosthetic joint infection. The motivation and goals behind antibiotic prophylaxis, current guidelines, the choice of antibiotic agents, and important factors in antimicrobial administration, including its dose, timing, and duration, are reviewed.