Before HIV became widespread, lumbar puncture was not routinely recommended for patients with untreated syphilis. According to the 1982 Centers for Disease Control and Prevention (CDC) guidelines,“... CSF examination should be done for patients with clinical symptoms or signs consistent with neurosyphilis. This examination is also desirable [emphasis mine] for other patients with syphilis of greater than 1 year’s duration...” Then, in the mid-to late 1980s and early 1990s, case reports and small series described “neurorelapse” in HIV-infected patients appropriately treated for early syphilis with benzathine penicillin G (BPG). These individuals developed early forms of neurosyphilis within weeks to months after BPG treatment. Similar results were not reported in patients without HIV infection. Such occurrences alerted practitioners to the possibility that the response to standard syphilis therapy, particularly with regard to development of overt neurologic disease, might be different in HIV-infected people compared with those without HIV. Although the magnitude of this problem was (and remains) unknown, many experts recommended that HIV-infected patients with any stage of syphilis should undergo lumbar puncture to identify and treat asymptomatic neurosyphilis to prevent neurorelapse. However, all did not embrace this recommendation, and it remains controversial to this day. In this volume of the Journal, Libois and colleagues report the results of a retrospective investigation of features that predict neurosyphilis in HIV-infected individuals with syphilis. 1 The criteria for neurosyphilis diagnosis included cerebrospinal fluid (CSF) white blood cells greater than or equal to 20/μL or a reactive CSF–Venereal Disease Research Laboratory (VDRL) or a positive ITPA index. These criteria are consistent with those used in clinical care. Twenty-six (23%) of 112 patients met the definition of neurosyphilis. Of note, 66 (59%) of the patients had late latent syphilis or syphilis of unknown duration and 46 (41%) of the patients had early syphilis. In a multivariate analysis, serum rapid plasma reagin (RPR) titer was significantly associated with increased odds of neurosyphilis; for every 2-fold increase in titer, the odds of neurosyphilis increased 1.4-fold. A receiver operator curve demonstrated that a serum RPR titer of 1: 32 or greater had the best sensitivity for diagnosis of asymptomatic neurosyphilis. Despite limitations of this study that include lack of uniform criteria for lumbar puncture, these data confirm those of our previous study, 2 and they add further support to the recommendation that all neurologically asymptomatic HIV-infected patients whose serum RPR titer is greater than or equal to 1: 32 should undergo lumbar puncture regardless of syphilis stage. The newly released 2006 CDC Sexually Transmitted Diseases Treatment Guidelines do not reflect these data. Specifically, lumbar puncture is recommended for asymptomatic HIV-infected individuals with late-latent syphilis or syphilis of unknown duration or for individuals who fail therapy for early or late syphilis. However, lumbar puncture is not routinely recommended for neurologically asymptomatic HIV-infected patients with early syphilis. The CDC’s rationale for this is that although “CSF abnormalities... are common in patients with early syphilis and in persons with HIV infection, the clinical and prognostic significance of... CSF abnormalities in HIV-infected patients with primary or secondary syphilis is unknown.” 3 This argument implies that if overt neurosyphilis were common in HIV-infected individuals with early syphilis, more cases would come to clinical attention. Because neurosyphilis is not a reportable disease …