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Root-end–filling materials have been tested for toxicity on several cell types, but their toxicity has not been tested on neurons. In this study we evaluated the neurotoxicity in murine cerebral cortical cell cultures of four commonly used root-end–filling materials: mineral trioxide aggregate, amalgam, Super EBA, and Diaket. Standardized amounts of each material were placed on culture-well inserts, allowing the material to be exposed to the culture bathing media without causing physical disruption of the cells. Cell death was quantified by assaying release of the cytosolic enzyme lactate dehydrogenase. Exposure of cortical cultures to freshly mixed or 7-day-old MTA did not cause significant neuronal death, whereas exposure to freshly mixed or 7-day-old amalgam, Super EBA, and Diaket resulted in significant neuronal death (p < .05). Thus, each material, except for mineral trioxide aggregate, can induce neurotoxicity, even when allowed to set thoroughly.