Inflammation has a significant role in the neurological injury that follows stroke. The receptor for advanced-glycation end products (RAGE) is a multiligand member of the immunoglobulin superfamily that has been implicated in multiple neuronal and inflammatory stress processes. To directly test the role of neuronal RAGE in stroke, we employed two cohorts of transgenic mice, one over-expressing full-length functional human RAGE in neurons, and the other a human RAGE transgene in which deletion of the cytoplasmic domain of the receptor in neurons suppresses signal transduction stimulated by ligands (referred to as dominant negative or DN-RAGE). We found a statistically significant increase in stroke volume in the RAGE over-expressing cohort compared to normal controls, and a trend towards decreased stroke volume in the DN RAGE cohort. These results indicate that RAGE signaling directly contributes to pathology in cerebral ischemia.