Recent studies indicate that human macrophages lack a high-output inducible nitric oxide synthase (NOS) antimicrobial system. In the present study, microglial cells derived from fetal human versus neonatal mouse brain were compared in a coculture assay of human and murine neuronal cell injury. Neurotoxicity (reflected by lactate dehydrogenase release and impaired neuronal uptake of [3H] gamma-amino butyric acid) and nitric oxide (NO) production (assessed by measurement of nitrite) were observed only in cocultures containing interferon (IFN)-gamma-lipopolysaccharide (LPS)-stimulated murine microglia. Cultures of purified human fetal microglia, however, did produce low levels of NO upon stimulation with IFN-gamma-LPS. These findings support the proposal that human macrophages have an inefficient IFN-gamma-inducible NOS and suggest that in tissues, such as brain, this deficiency could be advantageous for neighboring cells.