The effect of systemic administration of domoic acid, a potent structural analogue of kainic acid, on the mouse hippocampus has been studied using light and electron microscopic techniques. Intraperitoneal injections of either domoic acid (4 mg/kg) or kainic acid (32 mg/kg) produced a series of behavioural changes including sedation, rigidity, stereotypy (scratching, head nodding), balance loss, and discrete or generalized convulsions. Both qualitative and quantitative histological analysis revealed similar but not identical patterns of neuronal damage in the hippocampal formation of domoic acid- and kainic acid-treated mice. With both toxins the most extensive damage was always observed in the CA3 region of the hippocampus, with lesser degrees of damage observed in other hippocampal regions (CA4 greater than CA1 greater than CA2 greater than dentate granule cells). In general, neuronal damage was more widespread following administration of kainic acid than domoic acid. In the CA3 region, however, the percentage of cells exhibiting damage was greater following domoic acid (82.1%) than kainic acid (58.8%) following systemic administration. No damage was found in the hippocampi of vehicle control-treated mice. Electron microscopy of the CA3 region following domoic acid revealed two subpopulations of damaged neurons: (1) swollen cells that exhibited vacuolization of their cytoplasm and (2) shrunken irregularly shaped electron-dense cells. Swollen processes of astroglial origin were observed surrounding electron-dense cells, and electron-dense processes were often found extending into the neuropil. These results suggest that although domoic acid and kainic acid produce similar changes in both open field behaviour and hippocampal neuropathology, responses to these toxins are not identical at equitoxic doses. Lesions in the domoic acid-treated mice are more selective for the CA3 hippocampal region than are those produced by kainic acid following systemic administration. Domoic acid may, therefore, be a better tool for studying certain aspects of excitatory amino acid neurotoxicity.