Aluminum and mercury are common neurotoxic contaminants in our environment – from the air we breathe to the water that we drink to the foods that we eat. It is remarkable that to date neither of these two well-established environmental neurotoxins (i.e. those having a general toxicity towards brain cells) and genotoxins (those agents which exhibit directed toxicity toward the genetic apparatus) have been critically studied, nor have their neurotoxicities been evaluated in human neurobiology or in cells of the human central nervous system (CNS). In this paper we report the effects of added aluminum [sulfate; Al₂(SO₄)₃] and/or mercury [sulfate; HgSO4] to human neuronal-glial (HNG) cells in primary co-culture using the evolution of the pro-inflammatory transcription factor NF-kB (p50/p65) complex as a critical indicator for the onset of inflammatory neurodegeneration and pathogenic inflammatory signaling. As indexed by significant induction of the NF-kB (p50/p65) complex the results indicate: (i) a notable increase in pro-inflammatory signaling imparted by each of these two environmental neurotoxins toward HNG cells in the ambient 20-200 nM range; and (ii) a significant synergism in the neurotoxicity when aluminum (sulfate) and mercury (sulfate) were added together. This is the first report on the neurotoxic effects of aluminum sulfate and/or mercury sulfate on the initiation of inflammatory signaling in human brain cells in primary culture. The effects aluminum+mercury together on other neurologically important signaling molecules or the effects of other combinations of common environmental metallic neurotoxins to human neurobiology currently remain not well understood but certainly warrant additional investigation and further study in laboratory animals, in human primary tissue cultures of CNS cells, and in other neurobiologically realistic experimental test systems.