Although the accumulation of the neurotoxic peptide β amyloid (βA) in the CNS is a hallmark of Alzheimer's disease, the mechanism of βA neurotoxicity remains controversial. In cultures of mixed neurons and astrocytes, we found that both the full-length peptide βA (1–42) and the neurotoxic fragment (25–35) caused sporadic cytoplasmic calcium [intracellular calcium ([Ca²⁺]_c)] signals in astrocytes that continued for hours, whereas adjacent neurons were completely unaffected. Nevertheless, after 24 hr, although astrocyte cell death was marginally increased, ∼50% of the neurons had died. The [Ca²⁺]_c signal was entirely dependent on Ca²⁺ influx and was blocked by zinc and by clioquinol, a heavy-metal chelator that is neuroprotective in models of Alzheimer's disease. Neuronal death was associated with Ca²⁺-dependent glutathione depletion in both astrocytes and neurons. Thus, astrocytes appear to be the primary target of βA, whereas the neurotoxicity reflects the neuronal dependence on astrocytes for antioxidant support.