Apolipoprotein E (apoE, protein; APOE, gene) is expressed as three isoforms in humans (E2, E3, E4). The APOE-ε4 allele is associated with a poor outcome in patients after head injury of which ischaemic brain damage is a contributor of mortality and morbidity. The aim of the study was to determine whether mice expressing human APOE-ε4 displayed more extensive ischaemic neuronal damage 72 h after transient global ischaemia compared with mice which express human APOE-ε3. APOE-ε3 and -ε4 transgenic mice, under the control of a human promoter, were used which express human APOE in neurons and glia. Ischaemic neuronal damage in the CA1 pyramidal cell layer in the APOE-ε4 transgenic mice was significantly greater than in the APOE-ε3 mice after global ischaemia (36.4 ± 8.9%, 18.2 ± 7.3%; P < 0.05). This was associated with more extensive neuronal apoE immunoreactivity in the CA1 pyramidal cell layer in the APOE-ε4 transgenic mice compared with APOE-ε3 transgenic mice. In contrast, in the caudate nucleus, there were similar levels of ischaemic neuronal damage in the APOE-ε3 and -ε4 transgenic mice (39.2 ± 10.1%; 44.6 ± 8.4%, P = 0.32). In the caudate, similar numbers of neurons were immunostained for apoE in the APOE-ε3 and -ε4 transgenic mice. The present study demonstrated that the APOE-ε4 allele is associated with an increased vulnerability of a specific brain region to the effects of global ischaemia, which is closely associated with an increase in neuronal apoE. The data extend previous work and are consistent with an association of the APOE-ε4 allele with a poor outcome after acute brain injury in humans.