Interferon gamma (IFN-gamma) has been shown to be produced within multiple sclerosis (MS) lesions by infiltrating lymphocytes; systemic administration of this cytokine induces exacerbation of the disease. The aim of the current study was to establish the contribution of IFN-gamma to oligodendrocyte (OL) injury. Our studies utilized cultured human OLs, obtained by dissociation of surgically derived non-MS adult brain tissue. Neither cell survival nor myelin basic protein (MBP) gene expression were affected after 96 hours of treatment with IFN-gamma (100 U/ml), as assessed by LDH release, nucleosome enrichment assay, and RT-PCR. Expression of the death receptor Fas (CD95, APO-1) was, however, significantly increased. Furthermore, IFN-gamma-treated OLs became susceptible to Fas-mediated apoptosis when compared with untreated cells, and were protected by pretreatment with the caspase inhibitor ZVAD. TNF-alpha augmented the IFN-gamma-induced effect. Our results thus indicate that IFN-gamma is not directly cytotoxic for human OLs in culture, but could indirectly modulate functional injury-related responses by upregulating Fas on the cell surface.