A significant subset of patients treated for Lyme disease continue to have symptoms that persist for months or years. These may include pain, fatigue and neurocognitive problems, and collectively has been termed post-treatment Lyme disease syndrome. Whether these patients have ongoing infection is difficult to assess using current technology, and remains an open question. It is also possible that a post-infectious immune-mediated process may be responsible for continued symptoms. Here, the authors review central sensitization syndrome, in which pain and sensory processing is elevated. They discuss whether central sensitization may be related to continued symptoms in post-treatment Lyme disease.