HIV and aging have adverse effects on the central nervous system (CNS), including chronic inflammation, and confer risk for neurocognitive impairment (NCI) and functional decline. Cannabis may exert beneficial effects on the CNS in people with HIV (PWH) due to its anti-inflammatory and immunomodulatory properties. Yet to date, there is scant literature examining the role of cannabis and cannabinoids in this population. This staple dissertation aimed to elucidate the relationships among cannabis exposure, central and peripheral inflammation, and neurocognitive and functional impairment in PWH. Study 1 (N = 952; Watson et al., 2020). PWH with past-year cannabis use and past cannabis use disorder had lower rates of NCI (OR = 0.53, p = 0.009) and better performance in learning (b = 2.70, p = 0.02) and verbal fluency (b = 2.86, p = 0.02) compared to non-cannabis-using PWH. Cannabis use was unrelated to NCI among people without HIV. Study 2 (N = 234; Watson et al., 2021). Lower levels of pro-inflammatory biomarkers CCL2/MCP-1 and CLCX10/IP-10 in cerebrospinal fluid were observed among daily cannabis-using PWH with Δ9-tetrahydrocannabinol (THC) positive urine toxicology compared to non-cannabis-using PWH (p = 0.02; p = 0.04). Plasma biomarkers showed no differences by cannabis use. Lower levels of CCL2/MCP-1 and CLCX10/IP-10 were associated with better learning (b = –6.3, p = 0.02; b = –2.3, p = 0.04). Study 3 (N = 297; Watson et al., in preparation). In a longitudinal cohort of older adults with HIV, occasional cannabis use (≤ weekly) was associated with better overall global neurocognition (b = 0.50, p = 0.03), while THC+ urine toxicology showed negative short-term effects on memory (b = –0.27, p = 0.03). Rates of neurocognitive decline and functional declines did not differ by cannabis use. Collectively, these studies extend pre-clinical cannabinoid findings identifying beneficial cannabis effects on neuroinflammation and neurocognition in the context of HIV and THC-specific short-term detrimental impacts in older adults. Results highlight the complex influence of cannabis on CNS function, which varies by dose/frequency, cannabinoid content, and pro-inflammatory disease context, and can inform future development of cannabinoid-based therapeutics to treat neuroinflammation and improve downstream outcomes in HIV and aging.