CASE: A 68-year-old woman with a well-functioning total knee replacement presented with signs and symptoms of acute periprosthetic joint infection (PJI). Lyme serology and synovial fluid PCR were performed due to Borrelia burgdorferi. The patient was treated with oral doxycycline, had prompt resolution of symptoms, and remained asymptomatic 2 years later. CONCLUSION: Lyme PJI may be underappreciated as a cause of culture-negative PJI, cannot be diagnosed in routine culture, and can be cured without surgery.