A significant proportion of HIV-1 infected individuals develop a symptom complex consisting of dementia and motor deficits termed HIV Dementia (HTVD) or the AIDS Dementia complex (ADC). The pathophysiology of this neurologic complication is unclear, but neuronal injury and death may occur as a direct result of the release of cytokines from HIV-1 infected microglial cells (Everall et al, 1991). To evaluate the utility of a human neuronal cell line, NT2N, for studies of HTV-related neuronal cytotoxicity, we studied cellular viability after exposure to HIV-1 gp120, tumor necrosis factor α (TFNα), platelet activating factor (PAF), interleukin 1 beta (IL-1β), and interferon gamma (D7Nγ), all of which have been implicated in previous publications as having a role in HIVD (Brenneman et al, 1988; Dreyer ef al, 1990; Merrill ef al, 1992; Gelbard et al, 1993). Neither gp120 nor the cytokines IL-1β and IFNy resulted in significant NT2N cell death. However, TNFa and PAF were highly neurotoxic in this assay. Pentoxifylline, which inhibits the effects of TNFa, had a significant protective effect. This system provides an excellent subtrate for the evaluation of neurotoxicity and for the development of pharmacologic agents that may be useful in HIV dementia.