Long-term ethanol exposure leads to increases in the expression and/or sensitivity of NMDA-type glutamate receptors, effects that may contribute to the development of cytotoxicity in the brain. The human immunodeficiency virus 1 (HIV-1) transcription factor Tat is one of many viral proteins that may contribute to the development of HIV-associated dementia (HAD) by indirectly or directly promoting excess function of NMDA receptors. Thus, these studies examined the hypothesis that long-term ethanol pre-exposure would sensitize the hippocampus to Tat-induced cytotoxicity in an NMDA receptor-dependent manner.