The diagnosis of syphilis is dependent mainly on serological tests. In primary syphilis there is a seronegative period when the diagnosis is dependent on demonstration of Treponema pallidum in lesional exudate. The most widely used screening tests for syphilis are the VDRL and the rapid plasma reagin (RPR) and for confirmation the fluorescent treponemal antibody (FTA) and the treponema pallidum hemagglutination (TPHA) tests. The nonvenereal treponematoses have the same serological response as in syphilis. For the diagnosis of neurosyphilis, the cerebrospinal fluid (CSF) parameters available are insufficient. The albumin quotient for estimation of the blood-brain barrier function is recommended as well as the IgG index, which is a measure of intrathecal immunoglobulin production. Treponemal antibodies in CSF have high sensitivity for neurosyphilis, although the specificity is low. Although penicillin has been used as first-line therapy in syphilis for more than 40 years, T pallidum has not shown any signs of decreased sensitivity. T pallidum is still one of the most penicillin-sensitive microorganisms known. The standard treatment is depot preparations (benzathine penicillin and procaine penicillin) giving a continuous low penicillinaemia. Treatment failures in early syphilis have been exceedingly rare, although in neurosyphilis there have been several reports indicating that low-dose therapy is insufficient. With recommended treatment regimens, treponemicidal levels of penicillin in CSF are not achieved. Failure of therapy and rapid progression to neurosyphilis has recently been reported in patients coinfected with human immunodeficiency virus (HIV). It has been proposed that neurosyphilis and patients coinfected with syphilis and HIV should be treated with high intravenous doses of benzylpenicillin.