The rate of syphilis/HIV co-infection amongst men who have sex with men (MSM) in large urban regions ranges from 20 to 70%. Concurrent HIV infection can alter the clinical presentation of syphilis, the response to treatment, and complicate the diagnosis and clinical course of neurosyphilis. Therefore whether to perform a lumbar puncture (LP) on every co-infected patient in order to diagnose neurosyphilis is controversial. Current clinical guidelines specify the indications for LP, but fall short of recommending LP in certain clinical situations such as early syphilis without neurological involvement. This article reviews the current literature on the relative utility and indications for LP in syphilis/HIV co-infected patients and new research in this area.