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Aging and HIV have adverse effects on the central nervous system, including increased inflammation and neural injury and confer risk of neurocognitive impairment (NCI). Previous research suggests the nonacute neurocognitive effects of cannabis in the general population are adverse or null. However, in the context of aging and HIV, cannabis use may exert beneficial effects due to its anti-inflammatory properties. In the current study, we examined the independent and interactive effects of HIV and cannabis on NCI and the potential moderation of these effects by age.Participants included 679 people living with HIV (PLHIV) and 273 people living without HIV (HIV−) (18–79 years old) who completed neurocognitive, neuromedical, and substance use assessments. NCI was defined as a demographically corrected global deficit score ≥ 0.5. Logistic regression models examined the effects of age, HIV, cannabis (history of cannabis substance use disorder and cannabis use in past year), and their 2-way and 3-way interactions on NCI.In logistic regression models, only a significant interaction of HIV X cannabis was detected (P = 0.02). Among PLHIV, cannabis was associated with a lower proportion of NCI (odds ratio = 0.53, 95% confidence interval = 0.33–0.85) but not among HIV− individuals (P = 0.40). These effects did not vary by age.Findings suggest cannabis exposure is linked to a lower odds of NCI in the context of HIV. A possible mechanism of this result is the anti-inflammatory effect of cannabis, which may be particularly important for PLHIV. Further investigations are needed to refine the effects of dose, timing, and cannabis compound on this relationship, which could inform guidelines for cannabis use among populations vulnerable to cognitive decline.