Description: Background and Purpose— The Interventional Management of Stroke (IMS)-III trial randomized patients with acute ischemic stroke to intravenous tissue-type plasminogen activator (tPA) plus endovascular therapy versus intravenous tPA therapy alone within 3 hours from symptom onset. A predefined secondary hypothesis was that subjects with significant early ischemic change on the baseline scan would not respond to endovascular therapy. Methods— The primary outcome was 90-day modified Rankin Scale score 0 to 2. The baseline and follow-up computed tomographic (CT) scan images were reviewed centrally and blinded to any clinical information. We assessed whether the baseline Alberta Stroke Program Early CT Score (ASPECTS) predicted outcome and interacted with study treatment. We analyzed subgroups defined by time from onset to intravenous tPA initiation and baseline occlusion status at a prespecified α=0.01. Results— Baseline demographic and clinical characteristics of 656 randomized patients were similar between subjects with a baseline ASPECTS 8 to 10 (58% of the study sample) versus 0 to 7. Subjects with ASPECTS 8 to 10 were almost twice as likely (relative risk, 1.8; 99% confidence interval, 1.4–2.4) to achieve a favorable outcome. There was insufficient evidence of a treatment-by-ASPECTS interaction. In those treated with onset to intravenous tPA 〈120 minutes, in CT angiography–proven internal carotid artery or middle cerebral artery occlusion, and in both, results were similar. The probability of achieving recanalization (arterial occlusion lesion, 2–3) of the primary arterial occlusive lesion (relative risk, 1.3; 99% confidence interval, 1.0–1.8) or achieving thrombolysis in cerebral ischemia score 2b/3 reperfusion (relative risk 2.0; 99% confidence interval, 1.2–3.2) was higher among subjects with higher ASPECTS. Conclusions— ASPECTS is a strong predictor of outcome and a predictor of reperfusion. ASPECTS did not identify a subpopulation of subjects that particularly benefitted from endovascular therapy immediately after routine intravenous tPA. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00359424.