BACKGROUND Mycoplasma pneumoniae (M. pneumoniae) is a common pathogen for community-acquired pneumonia and is also implicated in a broad array of extra-pulmonary manifestations. M. pneumoniae infection is rarely associated with concurrent central nervous system (CNS) and peripheral nervous system (PNS) involvement in children. METHODS We report 2 patients who presented with acute encephalitis and polyradiculitis due to M. pneumoniae infection and review the literature to discuss the pathogenesis and treatment of concomitant CNS and PNS involvement associated with M. pneumoniae infection. RESULTS We report two 6-year-old boys with M. pneumoniae antecedent infection who presented initially with impaired consciousness followed by limb weakness, limb pain and urinary retention, and responded well to immunotherapy. CONCLUSIONS We described 2 patients who presented symptomatic combined CNS and PNS involvement with persistent urinary retention associated with M. pneumoniae infection. We found autoimmunity plays an important role and recommend that antibiotics and immunomodulators should be administered with concurrent CNS and PNS involvement associated with M. pneumoniae.