Post-menopausal persons living with HIV (PWH) report elevated levels of psychological stress and monocyte activation compared to persons living without HIV (PWOH). Resting state functional connectivity (rsFC) of mesolimbic brain regions underpinning stress and emotion regulation are susceptible to inflammatory insult. Although psychological stress is elevated, rsFC reduced, and CD16+ monocytes overexpressed in the brains of PWH, it is unclear whether the relationships amongst these variables differ compared to PWOH. An ethnically diverse sample of postmenopausal women, 24 PWH and 30 PWOH provided self-report mood surveys and provided peripheral blood specimens to quantify LPS-stimulated CD16+/- expression of TNF-α via flow cytometric analysis. An anatomical and resting state functional MRI scan were used to derive time-series metrics of connectivity between the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAcc) as well as the amygdala. A positive association was observed between levels of perceived stress and CD16+/- TNF-α in both LPS-stimulated and unstimulated cells. PLWH showed lower connectivity between mPFC and NAcc. In turn, lower rsFC between these regions predicted greater psychological stress and proportion of CD16-, but not CD16+, cells expression of TNF-α. Neuroimmune effects of monocyte inflammation on the functional connectivity of mesolimbic regions critical for discrimination of uncertainty-safety and reward signals were observed in an ethnically diverse sample of postmenopausal women living with and without HIV. PWH showed lower mPFC-NAcc functional connectivity, which in turn was associated with greater perceived stress.