Estrogen is a powerful neuroprotective agent in rodent models of ischemic stroke. However, in humans, estrogen treatment can increase risk of stroke. Health risks associated with hormone replacement have led many women to consider alternative therapies including high-soy diets or supplements containing soy isoflavones, which act as estrogen receptor ligands to selectively mimic some of estrogen's actions. We hypothesized that a high-soy diet would share the neuroprotective actions of estrogen in focal cerebral ischemia. Female Sprague-Dawley rats were ovariectomized and divided into three groups: isoflavone-free diet + placebo (IF-P), isoflavone-free diet + estradiol (IF-E), or high-soy diet + placebo (S-P). Two weeks after being placed on diets, rats underwent left permanent middle cerebral artery occlusion (MCAO). Reductions in ipsilateral cerebral blood flow were equivalent across groups ( approximately 50%). Twenty-four hours later neurological deficit was determined, and brains were collected for assay of cerebral infarct by TTC staining. In the IF-P rats MCAO produced a 50 +/- 4% cerebral infarct. Estrogen and high-soy diet both significantly reduced the size of the infarcts to 26 +/- 5% in IF-E rats and to 37 +/- 5% in S-P rats. Analysis at five rostro-caudal levels revealed that estrogen treatment was slightly more effective at reducing infarct size than high soy diet. Overall neurological deficit scores at 24 h correlated with infarct size; however, there were no statistically significant differences among the treatment groups. These data show that 2 wk of a high-soy diet is an effective prophylactic strategy for reducing stroke size in a rat model of focal cerebral ischemia.