Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) reduce the risk of myocardial infarction, stroke, and other vascular events, independent of cholesterol levels. Preliminary data from the Northern Manhattan Study also demonstrate reduced 90-day mortality in patients on statins at the time of ischemic stroke, as well as a trend toward reduced stroke severity. More recently, several statins have been shown in rodent stroke models to reduce infarct size, by both increasing cerebral blood flow through upregulation of endothelial nitric oxide synthase and reducing inflammation. Sequential Phase 1B and 2A trials of short-term high-dose simvastatin therapy in patients with acute ischemic stroke are proposed. A Phase 1B dose-escalation and dose-finding study will test the hypothesis that statin therapy is safe administered immediately after acute stroke at doses comparable to those used in animal studies of neuroprotection. Sixty patients over 2 years presenting within 12 hours of symptom onset will receive, in escalating blocks of patients, 1, 3, 5, 8, 10, 12,14,16,18, and 20 mg/kg of simvastatin daily for 3 days. The dose-escalation scheme will enroll more patients at higher dose levels, and will be updated based on the Continual Reassessment Method used in early-phase cancer clinical trials to optimize dose and maintain toxicity < 10%. The primary outcome will be development of clinical liver or muscle disease, or liver or muscle enzyme elevations >3X or >10X upper limit of normal, respectively. Pharmacokinetic assays will be performed. A safety monitoring committee will review blood pressure, neurological status, and rates of hemorrhagic conversion and infection for evidence of additional or unexpected toxicity. A Phase 2A randomized, placebo-controlled study (n=90 over 3 years) using the maximum-tolerated and an intermediate dose from Phase 1B will further confirm safety, and also explore for effects of statin therapy on functional outcome and inflammation. Patients receiving intravenous or intra-arterial thrombolysis will constitute approximately 2/3 of the patient population.