Neurosyphilis is a great imitator, and a clinician must be suspicious about the diagnosis as central nervous system infection may present in multivariate fashions. The abandonment of routine serological screening for syphilis has almost certainly reduced the frequency with which early diagnosis of syphilis is established. Concomitant immunosuppression, as occurs with HIV infection, may alter the clinical expression of syphilis. CSF VDRL cannot be used as the gold standard for diagnosis as it is often negative despite the presence of neurosyphilis. In this clinical article, Dr. Joseph Berger, Professor and Chairman of Neurology at the University of Kentucky, details the manifestations, diagnosis, and management of neurosyphilis.