The regional brain synthesis of prostaglandin E2 (PGE2) of rats varies with age and dietary vitamin E. We investigated ex-vivo synthesis of PGE2 in brain regions of 24-mo-old male C57BL/6Nia mice. Mice were fed semipurified diets containing 1) 5% by weight of vitamin E-stripped corn oil, nonhydrogenated coconut oil or fish oil, or 2) 3.8% lard + 1.2% stripped corn oil (control), each supplemented with 30 or 500 mg of vitamin E per kg for 6 wk. In addition, two groups of mice were fed control diets containing 2500 mg of ethoxyquin/kg or 1 mg of indomethacin/(kg.day). Mice fed fish oil had lower (P less than 0.01) plasma alpha-tocopherol than those fed coconut oil. Vitamin E supplementation had no effect on the concentration of alpha-tocopherol in most brain regions. The rank order of PGE2 synthesis among all groups was cerebrum = cerebellum greater than midbrain greater than brainstem. Vitamin E supplementation tended to reduce brain PGE2 synthesis. Fat with 30 mg/kg of vitamin E in their diet. In the brainstem, fish oil significantly reduced PGE2 relative to mice fed corn oil. Ethoxyquin lowered plasma alpha-tocopherol by 42% and reduced the PGE2 synthesis in brain regions, and indomethacin reduced it by 50%. Thus, ethoxyquin and indomethacin significantly reduced the brain's regional capacity for PGE2 synthesis, whereas vitamin E was not effective for the period tested. The reduction of PGE2 synthesis in the brain with fish oil feeding in this study was not as notable as reported for other tissues unless combined with high-dose vitamin E supplementation.