Apolipoprotein epsilon4 (apoE, protein; APOE, gene) allele is the most important genetic risk factor for development of Alzheimer's disease and is also associated with poor outcome after brain injury. Although the mechanisms underlying this susceptibility are currently unknown, recent experimental evidence suggests that APOE genotype may influence activity in the endocytic pathway of neurons. This study determined whether alterations in the endocytic pathway occurred in medial temporal lobe sections after brain injury because of cardiorespiratory arrest and whether these alterations were influenced by APOE genotype. Antibodies to two proteins involved in endocytosis, rabaptin-5 and rab4, were used as markers of endocytic pathway activity. Alterations in immunoreactivity were examined in medial temporal lobe sections in the postmortem brain of patients who experienced an episode of global ischemia and in controls. After global ischemia there was a marked increase in immunoreactivity of both endocytic markers, rabaptin-5 and rab4, in neurons, and to a lesser extent in glia compared to controls. Furthermore, possession of an APOE epsilon4 allele was associated with specific alterations in the endocytic pathway. After global ischemia, there was no influence of APOE genotype on the extent of rabaptin-5 immunoreactivity. However, there was a statistically significant influence of APOE genotype on the extent of rab4 immunoreactivity in response to global ischemia. These results indicate marked alterations in the endocytic pathway after global ischemia that are dependent on APOE genotype. This may underlie the important influence of APOE genotype on brain injury and disease.