Background and Purpose-We tested the hypothesis that early diffusion- and perfusion-weighted MRI (DWI and PWI, respectively) allows the prediction of malignant middle cerebral artery (MCA) infarction (MMI). Methods-Thirty-seven patients with acute MCA infarction and proximal vessel occlusion (carotid-T, MCA main stem) were studied by DWI, PWI, and MR angiography within 6 hours of symptom onset. Eleven patients developed MMI, defined by decline of consciousness and radiological signs of space-occupying brain edema. Lesion volumes were retrospectively defined as apparent diffusion coefficient <80% (ADC (<80%)) and time to peak >+4 seconds (TTP>+4s) compared with the unaffected hemisphere. ADC decrease within the infarct core (ADC(core)) and relative ADC within the ADC(<80%) lesion (rADC(lesion)) were measured. Neurological deficit at admission was assessed with the National Institutes of Health Stroke Scale (NIHSS). Results-Patients with MMI showed larger ADC(<80%) (median, 157 versus 22 mL; P<0.001) and TTP>+4s (208 versus 125 mL; P<0.001) lesion volumes, smaller TTP/ADC mismatch ratio (1.5 versus 5.5; P<0.001), lower ADC(core) values (290 versus 411 mm(2)/s; P<0.001), lower rADClesion (0.60 versus 0.66; P=0.001), higher frequency of carotid-T occlusion (64% versus 15%; P=0.006), and higher NIHSS score at admission (20 versus 15; P=0.001). Predictors of MMI were as follows for sensitivity and specificity, respectively: ADC(<80%) >82 mL, 87%, 91%; TTP>+4s > 162 mL, 83%, 75%; TTP/ADC mismatch ratio <2.4, 80%, 79%; ADC(core) < 300 mm(2)/s, 83%, 85%; rADC(lesion) <0.62, 79%, 74%; and NIHSS score at admission >= 19, 96%, 72%. Conclusions-Quantitative analysis of early DWI and PWI parameters allows the prediction of MMI and can help in the selection of patients for aggressive tissue-protective therapy.