Mycoplasma pneumoniae (M. pn.) commonly causes respiratory tract infections in humans. In a certain percentage of cases it may also be associated with various peripheral and central nervous system manifestations. We report a case of a 38-year-old previously healthy man who presented with hemiplegia and somnolence after he had suffered from a febrile respiratory infection 10 days earlier. Clinical features and laboratory investigations supported the diagnosis of an acute M. pneumoniae-associated meningoencephalitis. He was treated by an aggressive antibiotic and immunomodulatory regimen over the course of several weeks in the neurocritical care unit. Decompressive hemicraniectomy was performed due to life-threatening raised intracranial pressure. However, the patient recovered almost completely and presented with a mild neurological deficit after 3 months. Based on this case we give a review of the literature and discuss potential pathomechanisms and diagnostic approaches.