Monocytes transmigrating to the brain play a central role in HIV neuropathology. We hypothesized that the continued existence of neurocognitive impairment (NCI) despite potent antiretroviral (ARV) therapy is mediated by the inability of such therapy to control this monocyte/macrophage reservoir.Cross-sectional and longitudinal analyses were conducted within a prospectively enrolled cohort. We devised a monocyte efficacy (ME) score based on the anticipated effectiveness of ARV medications against monocytes/macrophages using published macrophage in vitro drug efficacy data. We examined, within an HIV neurocognitive database, its association with composite neuropsychological test scores (NPZ8) and clinical cognitive diagnoses among subjects on stable ARV medications unchanged for >6 months prior to assessment.Among 139 subjects on ARV therapy, higher ME score correlated with better NPZ8 performance (r=0.23, P<0.01), whereas a score devised to quantify expected penetration effectiveness of ARVs into the brain (CPE score) did not (r=0.12, P=0.15). In an adjusted model (adjusted r(2)=0.12), ME score (β=0.003, P=0.02), CD4(+) T-cell nadir (β=0.001, P<0.01) and gender (β=-0.456, P=0.02) were associated with NPZ8, whereas CPE score was not (β=0.003, P=0.94). A higher ME score was associated with better clinical cognitive status (P<0.01). With a range of 12.5-433.0 units, a 100-unit increase in ME score resulted in a 10.6-fold decrease in the odds of a dementia diagnosis compared with normal cognition (P=0.01).ARV efficacy against monocytes/macrophages correlates with cognitive function in HIV-infected individuals on ARV therapy within this cohort. If validated, efficacy against monocytes/macrophages may provide a new target to improve HIV NCI.