The tripeptide glutathione (reduced state, GSH) is an important intracellular free radical scavenger protecting cells against oxidative stress. The trisomy 16 mouse is a model of the human trisomy 21 (Down syndrome). Here we demonstrate that cultured hippocampal neurons from trisomy 16 mouse exhibit decreased GSH levels and augmented cell death when compared to diploid cells. Additional lowering of GSH levels led to enhanced cell death in trisomy 16 cells. Based on these results we suggest that a GSH level which is decreased under a specific threshold by increased consumption, reduced synthesis or lack in precursor contributes to cell loss and neurodegeneration in Down syndrome.