GLUTAMATE toxicity in retinal ganglion cells has well documented both in vitro and in vivo, and has been suggested to play a role in the neuronal loss in glaucoma. Of note, glaucoma selectively damages larger retinal ganglion cells first, and we therefore sought to explore whether glutamate-mediated cell death was likewise more pronounced in larger retinal ganglion cells. We now report that glutamate—which exerts its toxic effect on neurons predominantly through the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor—is more toxic to larger retinal ganglion cells both in tissue culture and in the intact rat eye. Cells smaller than 10 μm were relatively unaffected by glutamate or NMDA. These agents are, however, markedly toxic to retinal ganglion cells larger than 10 μm. These observations indicate that glutamate-mediated loss is seen first in larger retinal ganglion cells, in a similar fashion to the pattern of loss seen in glaucoma.