Objective: The current study examined the influence of host genotype on CSF cytokine soluble receptor (SR) levels and cognitive functioning in a sample of African American (AA) and European American (EA) HIV+ patients. Sequence variation in inflammatory-related genes and SR levels, may help to explain racial disparities in risk for HIV Associated Neurocognitive Disorder (HAND). Method: Participants were HIV+ African American (n = 44) and European American (n = 99) enrolled in the National Neurological Tissue Consortium. DNA was extracted from peripheral blood mononuclear cells. Genotyping was performed on IL-1, IL-6, IL-10, TNF-α, MCP-1 and MIP-1α. Soluble receptor quantification for IL-6-sRa, IL-1, TNF-R2, IL-2-sRa, and Baff was obtained from CSF samples. Biomarker assays were performed using multiplexed assay kits and software. AAs reported fewer years of education, and lower WRAT-3 scores than EAs. Results: EA were more likely to carry risk alleles associated with inflammation in IL-1 and IL-1RA than AA. AAs were more likely to carry the allele associated with low anti-inflammatory activity in IL-10 (p < .0001). Genotype was not associated with CSF SR levels or performance on NC. AAs demonstrated higher levels of TNF-R2. WRAT-3, TNF-R2, and ethnicity all predicted NC performance in a regression model. After controlling for WRAT-3 score, TNF-R2 and ethnicity/race continued to predict global NC. Conclusion(s): AAs were found to have elevated levels of CSF TNF-R2 that was associated with poor NC performance after controlling for education variables. Our results suggest that African Americans may be at greater risk for HAND due to greater expression of TNF-R2 in CSF.