Early growth response-1 (Egr1) is a sequence-specific transcription factor (TF) which is induced under hypoxic conditions. We presently report that transient middle cerebral artery occlusion (MCAO) leads to increased expression of Egr1 in the brains of adult mice and rats between 2 h and 5 days of reperfusion with a peak increase of 8-12-fold at 1 day. When subjected to transient MCAO and 3 days of reperfusion, Egr1-/- mice showed significantly smaller infarcts (by 44.9 +/- 8.4%, p < 0.05) and improved neurological function than Egr1+/+ littermates. Following transient MCAO, brains of Egr1-/- mice showed less water accumulation and decreased neutrophil infiltration (by 42 +/- 8%, p < 0.05) compared to Egr1+/+ mice. The number of activated microglia/macrophages were also significantly lower (OX42+ cells by 53 +/- 9%, p < 0.05 and ED1+ cells by 59 +/- 11%) in the post-ischemic cortex of Egr1-/- mice compared to Egr1+/+ mice. In addition, post-ischemic inflammatory gene expression was less pronounced in the brains of Egr1-/- mice compared to Egr1+/+ mice. Preventing cerebral Egr1 protein induction with small interference RNAs that target Egr1 decreased inflammatory gene expression and led to smaller infarcts (by 40.2 +/- 6.9%, p < 0.05) and reduced neurological deficits in rats subjected to transient MCAO. Conversely, transient MCAO following adenoviral-mediated Egr1 over-expression exacerbated the infarct volume (by 29 +/- 5.3%, p < 0.05) and worsened the neurological deficits in rats. These studies indicate Egr1 as a significant contributor of inflammation and neuronal damage after stroke.