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<h3>Objective.</h3> —To evaluate the efficacy and safety of intravenous thrombolysis using recombinant tissue plasminogen activator (rt-PA) in patients with acute ischemic stroke. <h3>Design.</h3> —Randomized, prospective, multicenter, double-blind, placebo-controlled clinical trial. <h3>Setting.</h3> —A total of 75 hospitals in 14 European countries. <h3>Patients.</h3> —A total of 620 patients with acute ischemic hemispheric stroke and moderate to severe neurologic deficit and without major early infarct signs on initial computed tomography (CT). <h3>Intervention.</h3> —Patients were randomized to treatment with 1.1 mg per kilogram of body weight of rt-PA (alteplase) or placebo within 6 hours from the onset of symptoms. <h3>Outcome Measures.</h3> —Primary end points included Barthel Index (BI) and modified Rankin Scale (RS) at 90 days. Secondary end points included combined BI and RS, Scandinavian Stroke Scale (SSS) at 90 days, and 30-day mortality. Tertiary end points included early neurologic recovery (SSS) and duration of in-hospital stay. Safety parameters included mortality and incidence of intracranial or extracranial hemorrhage. <h3>Results.</h3> —The distribution of demographic variables was similar among patients in the rt-PA and placebo treatment arms in both the intention-to-treat (ITT) analysis and the explanatory analysis for the target population (TP). A total of 109 patients (17.4%) were included in the trial despite major protocol violations but excluded from the TP. There was no difference in the primary end points in the ITT analysis, while the TP analysis revealed a significant difference in the RS in favor of rt-PA—treated patients (<i>P</i><.035). Of the secondary end points, the combined BI and RS showed a difference in favor of rt-PA—treated patients in both analyses (<i>P</i><.001). Neurologic recovery at 90 days was significantly better for rt-PA—treated patients in the TP (<i>P</i>=.03). The speed of neurologic recovery assessed by the SSS was significantly better up to 7 days in the ITT analysis and up to 30 days for the TP in the rt-PA treatment arm. In-hospital stay was significantly shorter in the rt-PA treatment arm in both analyses. There were no statistically significant differences in the mortality rate at 30 days or in the overall incidence of intracerebral hemorrhages among the rt-PA and placebo treatment arms in either analysis. However, the occurrence of large parenchymal hemorrhages was significantly more frequent in the rt-PA—treated patients. <h3>Conclusions.</h3> —Intravenous thrombolysis in acute ischemic stroke is effective in improving some functional measures and neurologic outcome in a defined subgroup of stroke patients with moderate to severe neurologic deficit and without extended infarct signs on the initial CT scan. However, the identification of this subgroup is difficult and depends on recognition of early major CT signs of early infarction. Therefore, since treating ineligible patients is associated with an unacceptable increase of hemorrhagic complications and death, intravenous thrombolysis cannot currently be recommended for use in an unselected population of acute ischemic stroke patients. (<i>JAMA</i>. 1995;274:1017-1025)