Inclusion Criteria:

• Age: 18 through 82 years (i.e., candidates must have had their 18th birthday, but not their 83rd birthday).
• Initiation of IV rt-PA within 3 hours of onset of stroke symptoms. Time of onset is defined as the last time when the patient was witnessed to be at baseline (i.e., subjects who have stroke symptoms upon awakening will be considered to have their onset at beginning of sleep).
• An NIHSSS ≥ 10 at the time that IV rt-PA is begun or an NIHSSS >7 and <10 with an occlusion seen in M1, ICA or basilar artery on CTA at institutions where baseline CTA imaging is standard of care for acute stroke patients.
• Investigator verification that the subject has received/ is receiving the correct IV rt-PA dose for the estimated weight prior to randomization

Exclusion Criteria:

• History of stroke in the past 3 months.
• Previous intra-cranial hemorrhage, neoplasm, subarachnoid hemorrhage, or arteriovenous malformation.
• Clinical presentation suggests a subarachnoid hemorrhage, even if initial CT scan is normal.
• Hypertension at time of treatment; systolic BP > 185 or diastolic > 110 mm Hg; or aggressive measures to lower blood pressure to below these limits are needed.
• Presumed septic embolus, or suspicion of bacterial endocarditis
• Presumed pericarditis including pericarditis after acute myocardial infarction.
• Suspicion of aortic dissection
• Recent (within 30 days) surgery or biopsy of parenchymal organ.
• Recent (within 30 days) trauma, with internal injuries or ulcerative wounds.
• Recent (within 90 days) severe head trauma or head trauma with loss of consciousness.
• Any active or recent (within 30 days) hemorrhage.
• Patients with known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency; or oral anticoagulant therapy require coagulation lab results prior to enrollment. Any subject with INR greater than 1.7 or institutionally equivalent prothrombin time is excluded. Patients without history or suspicion of coagulopathy do not require INR or prothrombin time lab results to be available prior to enrollment.
• Females of childbearing potential who are known to be pregnant and/or lactating or who have positive pregnancy tests on admission.
• Baseline lab values: glucose < 50 mg/dl or > 400 mg/dl, platelets <100,000, or Hct <25
• Patients that require hemodialysis or peritoneal dialysis, or who have a contradiction to an angiogram for whatever reason .
• Patients who have received heparin or a direct thrombin inhibitor (Angiomax™ or argatroban, Refludan™) within 48 hours must have a normal partial thromboplastin time (PTT) to be eligible.
• Subjects with an arterial puncture at a non-compressible site or a lumbar puncture in the previous 7 days.
• Patients with a seizure at onset of stroke
• Patients with a pre-existing neurological or psychiatric disease that would confound the neurological or functional evaluations, mRS score at baseline must be < 2. This excludes patients who live in a nursing home or who are not fully independent for activities of daily living (toileting, dressing, eating, cooking and preparing meals, etc.)
• Other serious, advanced, or terminal illness.
• Any other condition that the investigator feels would pose a significant hazard to the patient if Activase (Alteplase) therapy is initiated.
• Current participation in another research drug treatment protocol.
• Informed consent is not or cannot be obtained. For example, obtunded patients are not automatically excluded from the study. However, if the next of kin or legal guardian (i.e., the individual legally empowered in the state where the consent is obtained) cannot provide consent, randomization and entry into the study could not proceed.

IMAGING Exclusion Criteria:

• High density lesion consistent with hemorrhage of any degree.
• Significant mass effect with midline shift.
• Large (more than 1/3 of the middle cerebral artery) regions of clear hypodensity on the baseline imaging. An ASPECTS of < 4can be used as a guideline when evaluating >1/3 region of territory involvement. Sulcal effacement and / or loss of grey-white differentiation alone are not contraindications for treatment.