Persistent symptoms following appropriate treatment of confirmed Lyme borreliosis (LB) require a systematic clinical reassessment. The diagnostic approach should verify the accuracy of the initial diagnosis, adherence to and adequacy of antibiotic therapy, and consider potential sequelae or differential diagnoses such as new-onset diseases or comorbidities. When no alternative explanation is found, symptoms may correspond to Post-Treatment Lyme Disease Syndrome (PTLDS), as defined by the French National Authority for Health (HAS). PTLDS is characterized by fatigue, diffuse pain, and cognitive dysfunction lasting more than six months after a documented and adequately treated LB episode. The syndrome significantly impairs daily functioning and quality of life and is not attributable to persistent infection or other identifiable causes. Management relies on long-term, multidisciplinary, and personalized care coordinated between reference centers and primary physicians, focusing on physical rehabilitation and psychological support. Additional antibiotic or immunomodulatory therapies are not recommended due to lack of efficacy and potential adverse effects. Future research should prioritize high-quality clinical studies to clarify therapeutic indications, integrate social science perspectives to better understand the illness and its controversies, and actively involve patients to ensure that research and care strategies align with their lived experiences.