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The persistence of human immunodeficiency virus-1 (HIV)-associated neurocognitive disorders (HAND) in the era of effective antiretroviral therapy suggests that modern HIV neuropathogenesis is driven, at least in part, by mechanisms distinct from the viral life cycle. Identifying more subtle mechanisms is complicated by frequent comorbidities in HIV + populations. One of the common confounds is substance abuse, with cannabis being the most frequently used psychoactive substance among people living with HIV. The psychoactive effects of cannabis use can themselves mimic, and perhaps magnify, the cognitive deficits observed in HAND; however, the neuromodulatory and anti-inflammatory properties of cannabinoids may counter HIV-induced excitotoxicity and neuroinflammation. Here, we review our understanding of the cross talk between HIV and cannabinoids in the central nervous system by exploring both clinical observations and evidence from preclinical in vivo and in vitro models. Additionally, we comment on recent advances in human, multi-cell in vitro systems that allow for more translatable, mechanistic studies of the relationship between cannabinoid pharmacology and this uniquely human virus.