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Background Human immunodeficiency virus (HIV) infection leads to blood–brain barrier (BBB) dysfunction that does not resolve despite viral suppression on antiretroviral therapy (ART) and is associated with adverse clinical outcomes. In preclinical models, cannabis restores BBB integrity. Methods We studied persons with HIV (PWH) and HIV-negative (HIV−) individuals who had used cannabis recently. We assessed 2 biomarkers of BBB permeability: the cerebrospinal fluid (CSF) to serum albumin ratio (CSAR) and CSF levels of soluble urokinase plasminogen activator receptor (suPAR), a receptor for uPA, a matrix-degrading proteolytic enzyme that disrupts the BBB. A composite index of the BBB markers was created using principal components analysis. Neural injury was assessed using neurofilament light (NFL) in CSF by immunoassay. Results Participants were 45 PWH and 30 HIV− individuals of similar age and ethnicity. Among PWH, higher CSF suPAR levels correlated with higher CSAR values (r  = 0.47, P  < .001). PWH had higher (more abnormal) BBB index values than HIV− individuals (mean ± SD, 0.361 ± 1.20 vs −0.501 ± 1.11; P  = .0214). HIV serostatus interacted with cannabis use frequency, such that more frequent use of cannabis was associated with lower BBB index values in PWH but not in HIV− individuals. Worse BBB index values were associated with higher NFL in CSF (r  = 0.380, P  = .0169). Conclusions Cannabis may have a beneficial impact on HIV-associated BBB injury. Since BBB disruption may permit increased entry of toxins such as microbial antigens and inflammatory mediators, with consequent CNS injury, these results support a potential therapeutic role of cannabis among PWH and may have important treatment implications for ART effectiveness and toxicity. [ABSTRACT FROM AUTHOR]