BACKGROUND: A retrospective study was conducted in people with HIV (PWH) to explore potential cerebrospinal fluid (CSF) biomarkers linked to CSF neurofilament light levels (NfL), indicative of neuronal injury. METHODS: A sample of 168 participants was tested, including 43 HIV-negative controls and PWH who were classified into subgroups based on HIV and treatment status. Twenty CSF protein biomarkers were analyzed for their association with CSF NfL concentrations using a linear regression forward selection strategy, adjusted for age and sex. Regression trees were utilized to visualize feature relationships. RESULTS: Age-adjusted average concentrations of CSF NfL ranged from 427 pg/mL (SD = 190) in HIV- participants to 6456 pg/mL (SD = 46,024) in participants with HIV-associated dementia. Significant associations were found between specific biomarkers and CSF NfL levels in different participant subgroups. Noteworthy findings included correlations between CSF t-tau, CSF MCP-1, CSF TNF-α, and albumin ratio with CSF NfL levels in untreated PWH, and CSF IL-21 with CSF NfL in treated, virally suppressed PWH. Association between age and CSF NfL concentrations was a general finding. CONCLUSION: We identified specific CSF biomarkers, including CSF t-tau protein, CSF MCP-1, and CSF TNF-α that associated with CSF NfL concentrations in untreated PWH and CSF IL-21 that associated with CSF NfL in PWH with effective treatment, shedding light on neuroinflammatory processes which may underlie HIV-related neuronal injury and the impact of antiviral therapy. Further investigations are needed to validate if elevated CSF IL-21 concentrations persist during long-term treatment, and if particular drug combinations are optimal for decreasing inflammatory latency.