Memantine, a low-to-moderate-affinity NMDA receptor antagonist, can be used to treat cognitive impairment associated with Alzheimer's disease. However, its potential neuroprotective effects for human immunodeficiency virus type 1-associated (HIV-1-associated) dementia are less well appreciated. To this end we studied hippocampal synaptic function in a severe combined immunodeficient (SCID) mouse model of HIV-1 encephalitis (HIVE). Human monocyte-derived macrophages (MDMs) infected with HIV-1(ADA) were injected stereotactically into the caudate and putamen of SCID mice, generating HIVE. These brain subregions are among those most affected in humans. Impaired synaptic transmission and long-term potentiation (LTP) were detected in the CA1 region of hippocampal brain slices of HIVE mice. Memantine-treated HIVE mice showed significant improvements in synaptic function during frequency facilitation tests and LTP induced by high-frequency stimulation when compared with untreated animals. Immunocytochemical measures of neuronal antigens mirrored the neuronal physiological tests. These results demonstrate that memantine attenuates hippocampal synaptic impairment in murine HIVE and provide a rationale for its use in infected humans who experience cognitive decline.