Background: Statins have been demonstrated to reduce ischemic stroke. Intensive therapy with ezetimibe/simvastatin (E/S) in IMPROVE-IT significantly reduced the occurrence of cardiovascular events in patients post ACS compared to placebo/simvastatin (S). We evaluated the effect of E/S vs S on stroke outcomes. Methods: We determined the KM-rate of stroke, by type,during the median 6 year follow-up in 18,144 patients treated with E/S vs S in the IMPROVE-IT trial. Stroke was adjudicated and divided into non-hemorrhagic (NH), hemorrhagic (H), or unknown (U) by a blinded clinical event committee. Stroke reductions were adjusted to absolute change in LDL-C for comparison to prior studies. Results: There were 641 (3.5%) subjects with stroke during follow up, including 533 non-hemorrhagic, 102 hemorrhagic, and 14 unknown strokes. Overall, stroke tended to be reduced with E/S (4.2 vs 4.8%; HR 0.86, CI 0.73-1.00, p=0.052), with a significant reduction of NH stroke (3.4 vs 4.1%; HR 0.79, CI 0.67-0.94, p=0.008, Figure), but a numerical increase in H stroke (0.8 vs 0.6%; HR 1.38, CI 0.93-2.04, p=0.11, Figure). Results were similar when NH/U strokes were combined. When adjusted for LDL reduction, the NH stroke reduction appears to be similar to greater than the extent previously reported with statin therapy alone (figure). Reductions in NH strokes were consistent across major demographic and lipid subgroups. Of note, in 1071 patients with prior stroke or TIA, a known high-risk group, the absolute benefit of E/S was particularly marked for NH strokes; 9.9vs 14.7% (HR 0.61 (0.41-0.91, NNT 21), though benefit remained in those without prior stroke 3.1 vs 3.5% (HR 0.84, CI 0.70-1.01, NNT 250, Pint=0.16). No difference in hemorrhagic stroke was noted in either group. Conclusions: Lipid lowering therapy with E/S was superior to S in the incidence of non-hemorrhagic stroke through a median of 6 years; there was a large absolute benefit in patients with prior stroke or TIA.