BACKGROUND: Approximately 10% of patients experience prolonged symptoms after Lyme disease. PTLDS (post treatment Lyme disease syndrome) is a controversial topic. It has been described as a source of overdiagnostic and off-label treatment. The objective of this work was to describe, in the context of the PTLDS, the diagnostic errors and adverse effects of drugs used outside the recommendations. METHODS: systematic review of the literature according to PRISMA criteria, including randomized clinical trials (RCT), observational studies, and case reports addressing diagnostic errors and adverse events published between January 2010 and November 2020 in English or French. RESULTS: 16 studies were included: 1 RCT, 7 observational studies and 8 case reports. In the 5 observational studies, overdiagnosis rates were very high, ranging from 80% to 100%. The new diagnoses were often psychiatric, rheumatological and neurological. Disorders with somatic symptoms were often cited. Diagnostic delays were identified for cancers and frontoparietal dementia. In the RCT and observational studies, prolonged anti-infective treatments were also responsible for adverse events, with emergency room visits and/or hospitalization. The most common adverse events were diarrhea, sometimes with Clostridium difficile colitis, electrolyte abnormalities, sepsis, bacterial and fungal infections, and anaphylactic reactions. CONCLUSION: This review informs patients and physicians of the risks of prolonged anti-infective treatment that has not been proven to be beneficial. It does not seem ethical to offer such treatments to patients given the imperative of the "primum non nocere" principle of non-maleficence.