A novel mediator of vascular function and cerebrovascular blood flow are CYP450 derived epoxyeicosatrienoic acids (EETs). EETs are endothelial derived hyperpolarizing factors produced by endothelial and neuronal cells and EETs are converted by soluble epoxide hydrolase (SEH) enzyme to less active diols. We have shown that adamantanyl dodecanoic acid (AUDA), a SEH inhibitor, can protect against cerebral ischemia and increase middle cerebral artery (MCA) compliance in spontaneously hypertensive stroke prone rats (SHR-SP). Here we show that 6 weeks of 50mg/L of AUDA in drinking water also reduces percent hemispheric infarct size in Wistar Kyoto rats with 6 hours of permanent MCA occlusion (8.2±1.5 n=12 in AUDA treated versus (vs.) 19.7±5.3 in controls n=11, P<0.05), which correlates with the smaller neurodeficit score 4.9±0.3 in AUDA treated vs. 5.6±0.2 control (P<0.05). Systolic blood pressure was unaltered in AUDA treated WKY rats 144±2 n=10 versus control WKY rats 143±3 n=8 and SHR-SP 233±14 n=4 versus control SHR-SP rats 212±5 n=5. Six weeks of AUDA did not alter MCA wall to lumen ratio (W/L) in WKYs (0.15±0.01 n=4 treated vs. 0.16±0.02 n=5 control). The W/L was reduced in SHR-SP (0.20±0.01 n=4 treated vs. 0.25±0.03 n=5 control) and less collagen staining was detected in SHR-SP MCA. These results suggest that SEH inhibition reduces pathological vascular remodeling and is protective during acute cerebral ischemia.