Transgenic mice were created using human apolipoprotein E2, E3, and E4 gene fragments driven by the human glial acidic fibrillary protein (GFAP) promoter. Founders were obtained and progeny were assayed for transgene expression in the brain by RNase protection, immunohistochemistry, and Western blotting, demonstrating robust apolipoprotein E (apoE) brain expression, with human apoE representing up to approximately 0.2% of total brain protein. Selected lines were bred to apoE-deficient mice yielding mice which expressed the human transgenic apoE isoforms in the absence of endogenous apoE. Immunohistochemistry revealed accumulation of the transgene encoded human apoE throughout the brain. Double immunofluorescence showed co-expression of the apoE transgene with endogenous glial acidic fibrillary protein. Primary astrocyte cultures from the transgenic mice secreted human apoE into the medium. Aged apoE4 transgenic mouse brain failed to demonstrate any evidence of senile plaques. These mice may be useful for elucidation of the mechanism by which apoE4 is associated with Alzheimer's disease.