Background: Both family history of dementia (FHD) and lower levels of Aβ-42 are indepentently associated with worse neurocognitive functioning in HIVinfected patients. Objective: To examine the relationships between cerebrospinal fluid (CSF) Aβ-42 and FHD with HIV-associated neurocognitive disorders (HAND). Methods: One hundred eighty-three HIV+ adults underwent neuropsychological and neuromedical assessments, and determination of CSF Aβ-42 concentration and FHD (defined as a self-reported first or second-degree relative with a dementia diagnosis). Univariate analyses and multivariable logistic regressions were used. Results: FHD was not associated with HAND (p = 0.24); however, CSF Aβ-42 levels were lower (p = 0.03) in the HAND group, but were not associated with FHD (p = 0.89). Multivariable models showed a main effect of CSF Aβ-42 (p = 0.03) and a trend-level (p = 0.06) interaction between FHD and CSF Aβ-42, such that lower CSF Aβ-42 was associated with HAND in those with FHD (p < 0.01) compared to those without FHD (p = 0.83). An analysis in those with follow-up data showed that higher baseline CSF Aβ-42 was associated with lower risk of neurocognitive decline (p = 0.02). While we did not find an FHD X CSF Aβ-42 interaction (p = 0.83), when analyses were stratified by FHD, lower CSF Aβ-42 was associated at the trend-level with neurocognitive decline in the FHD group (p = 0.08) compared to the no FHD group (p = 0.15). Conclusion: FHD moderates the relationship between of CSF Aβ-42 and HAND. The findings highlight the complexities in interpreting the relationships between biomarkers of age-related neurodegeneration and HAND.