Down's syndrome, a congenital disorder associated with cognitive impairment and early-onset Alzheimer's disease, is a progressive genetic pathology resulting from full or partial triplication of chromosome 21. Down's syndrome brain is typified by activated microglia, increases in inflammatory signaling, and an aberrant immune system. In these studies, a screening of micro-RNA (miRNA) from Down's syndrome brain and peripheral tissues indicated an upregulation of a chromosome 21-encoded miRNA-155 and a decrease in the abundance of the miRNA-155 mRNA target complement factor H (CFH), an important repressor of the innate immune response. Stressed primary human neuronal-glial cells indicated both miRNA-155 increase and CFH downregulation, an effect that was reversed using anti-miRNA-155. These findings suggest that immunopathological deficits associated with Down's syndrome can, in part, be explained by a generalized miRNA-155-mediated downregulation of CFH that may contribute to both brain and systemic immune pathology.