Studies with in vitro model systems suggest that at least part of the neurologic deficits of human immunodeficiency virus (HIV)-1-associated cognitive/motor complex may stem from neuronal injury mediated by the HIV-1 coat protein gp120. Concurrent activation of N-methyl-D-aspartate (NMDA) receptors is also necessary for gp120 to induce neuronal damage. We studied memantine, a drug that blocks NMDA receptor-operated ion channels, for possible protective effects from gp 120-induced neuronal injury. In identified rat retinal ganglion cells in culture, we found that 2 FM memantine completely prevented the injury engendered by 20 pM gp120. These data suggest that memantine has therapeutic potential as an NMDA antagonist capable of ameliorating neuronal damage associated with gp120.