Neurosyphilis is any involvement of the central nervous system (CNS) by Treponema pallidum. The CNS may be involved at any stage of infection.A 54-year-old previously healthy African American male was hospitalized due to a two-year history of progressive cognitive decline. One year after symptoms began, he developed, over a four-month period, gait disturbance resulting in frequent falls, speech impairment, worsening memory loss, psychosis, and an inability to perform activities of daily living.A diagnosis of neurosyphilis was established upon cerebrospinal fluid (CSF) positive results and new changes in his mental status. The CSF showed predominant lymphocytic pleocytosis (17), elevated protein (111), and IgG index (4.25). Other viral and bacterial panels were negative. Intravenous penicillin G, 24 million units daily for 14 days, was given. Two months later, the patient was transferred to the hospital for altered behavior and mental status changes from the cognitive baseline. The repeat CSF rapid plasma reagin (RPR) titer (1:4) was the same as at initial diagnosis, despite appropriate treatment. Brain MRI showed progressive volume loss in both temporal lobes, thalamus, and cerebellum, consistent with evolving encephalitis. Treatment with intravenous penicillin G, 24 million units, was repeated. The patient improved clinically.Hence, in emerging cases of syphilis, this patient has been diagnosed with a neurosyphilis flare, unresponsive to the usual dose and duration of penicillin. We recommended a repeat CSF examination every six months and having a lower threshold for CSF examination for possible flare or resistance. Our case showed a failure to respond to the usual course of penicillin, requiring a second course of IV Penicillin G, although no resistance to penicillin has been reported.