Spudich S, et al. - HIV persistence in cerebrospinal fluid (CSF) and how it relates to inflammation and neurocognitive performance during long-term antiretroviral therapy (ART) were examined. Concurrent lumbar puncture, phlebotomy, and neurocognitive assessment were done among participants enrolled in the AIDS Clinical Trials Group HIV Reservoirs Cohort Study (A5321). In peripheral blood mononuclear cells and in cell pellets from CSF, cell-associated HIV DNA and HIV RNA (CA-DNA, CA-RNA) was quantified by quantitative PCR (qPCR). After a median 8.6 years of ART, assessment of CSF in 69 participants (97% male, median age 50 years, CD4 696 cells/mm³, plasma HIV RNA <100 copies/mL) revealed cell-free RNA in 4%, CA-RNA in 9%, and CA-DNA in 48% (median level 2.1 copies/10³ cells). This suggests that almost half of individuals on long-term ART show persistent HIV-infected cells in CSF, and their discovery is linked with worse neurocognitive performance.