HIV-associated neurocognitive disorders persist despite early antiretroviral therapy (ART) and optimal viral suppression. We examined the relationship between immunopathogenesis driven by various pathways of immune activation and discrete neurocognitive performance domains in youth with HIV (YWH). Observational cross-sectional study METHODS:: YWH, ages 20 to 28, enrolled in Adolescent Medicine Trials Network 071/101 were assessed for biomarkers of macrophage, lymphocyte activation and vascular inflammation using ELISA/multiplex assays. Standardized neurocognitive tests were performed, and demographically-adjusted z-scores were combined to form indices of attention, motor, executive function, verbal and visuospatial memory. Cross-sectional analysis of the relationship between 18 plasma inflammatory biomarkers and each neurocognitive domain was performed. Linear regression models were fit for each combination of log-transformed biomarker value and neurocognitive domain score, and were adjusted for demographics, socioeconomic status, substance use, depression, CD4 T cell count, HIV viral load, and ART status. Study included 128 YWH [mean age 23.8 (SD 1.7) years, 86% men, 68% African American]. Verbal and visuospatial memory domains were most significantly impaired in the cohort (z = -1.59 and -1.0, respectively). Higher sCD14 was associated with impaired visuospatial memory, which remained robust after adjusting for other biomarkers, demographics, and HIV-associated covariates. Among biomarkers of vascular inflammation, sICAM-1 was negatively associated with verbal memory and attention, while sVCAM-1 was positively associated with executive function and visuospatial memory. Specific neurocognitive domains were not associated with sCD163, LPS, or CCL2 levels. Impaired visuospatial memory in YWH is associated with immune activation, as reflected by higher sCD14.