Large supratentorial infarctions play an important role in early mortality and severe disability from stroke. However, data concerning these types of infarction are scarce. Using data from the Lausanne Stroke Registry, we studied patients with a CT-proven infarction of the middle cerebral artery (MCA) territory that covered at least two of three MCA subterritories (deep, superficial anterior [superior] and posterior [inferior] territory). We compared these patients with patients presenting more limited infarction in the MCA territory. Our study group of large MCA (laMCA) infarction contained 208 patients, corresponding to 7.6% of all ischemic infarctions in the Lausanne Stroke Registry. Seventy-two patients had complete infarction in the whole MCA territory (coMCA). Internal carotid artery (ICA) occlusion (41%) and ICA dissection (12%) were more common than in limited superficial MCA (lsMCA) infarct and anterior circulation infarct (p < 0.001). Among the patients without ICA occlusion, atrial fibrillation (33%; p < 0.002) and cardiogenic embolism in general (54%; p < 0.001) were more frequent in laMCA than in lsMCA infarct. Severe neurologic deficit (hemiplegia and hemisensory loss in the face, arm and leg, hemianopia, global aphasia, reduced consciousness) was more common than in other types of infarct. A combination of these symptoms had a positive predictive value for laMCA infarction of 0.73 (sensitivity for left side laMCA infarcts, 0.56). Mortality (17%) and severe disability (50%) were higher with laMCA than for other infarcts (p < 0.001). Sixteen of the 35 deaths could be attributed to brain edema. Reduced consciousness, hemianopia, and coMCA infarction were independent predictors of death or severe disability; for death only, coma was an independent predictor. Patients who died because of brain edema were younger than patients whose death was due to other causes (mean age, 57 versus 73 years; p < 0.001); they also died sooner (mean time of death after stroke, 5 versus 37 days; p < 0.001). Furthermore, patients who developed coma on the day of admission were more likely to die because of brain death (p < 0.001). Large middle cerebral artery infarction is associated with cardiogenic embolism, ICA occlusion, and ICA dissection. It is a major predictor of death and severe disability, although a lower frequency of malignant brain infarction was found than previously reported.