APOE polymorphism may influence risk for cold sores and, by interacting with latent HSV-1, risk for Alzheimer's disease (AD). APOE genotype also influences outcome after brain injury. We sought to determine whether APOE genotype influences risk for herpes simplex encephalitis (HSE), whether apoE is involved in the response to HSE and if APOE genotype influences outcome from HSE. There was increased immunoreactivity of neurons, neuropil and glia for apoE areas of brain damaged by HSE. APOE genotypes for cases of HSE (n = 57) were similar to those of controls (n = 41). APOE genotypes for survivors of HSE were similar to those of patients who died. We conclude that apoE is involved in the response to damage associated with HSE, as in other forms of brain injury. However, APOE genotype does not appear to influence either the risk of developing HSE or subsequent mortality.