From several disease states as well as from animal models homocysteine is known to be toxic to the central nervous system. Homocysteine is an excitatory amino acid which markedly enhances the vulnerability of neuronal cells to excitotoxic, apoptotic, and oxidative injury in vitro and in vivo. Both beneficent and deleterious effects of astrocytes in the pathogenesis of different neurodegenerative disorders have been described. However, data about the neurotoxic effect of homocysteine on astrocytes are lacking. The present study therefore was undertaken to investigate a possible cytotoxic effect of homocysteine on cortical astrocytes in vitro. Exposure to D,L-homocysteine resulted in a time and dose-dependent gliotoxic effect at doses of 2 mM and above (P<0.001). This is comparable to homocysteine toxicity observed in other cell culture models and implies that a participation of astrocytes in homocysteine-induced neurodegeneration may be considered. The results of the present in vitro studies may therefore have implications for understanding the pathogenesis of neurotoxicity linked to neurodegenerative disorders (e.g. Alzheimer's disease, glaucomatous optic neuropathy). This is the first study to report that homocysteine induces cell death of astrocytes. The mechanisms by which homocysteine induces cell death of astrocytes warrant further study.