Background and Purpose - Early predictors of infarct volume may improve therapeutic decisions in patients with acute cerebral ischemia. We investigated whether measurements of serum astroglial protein S100B can predict a malignant course of infarction in acute middle cerebral artery (MCA) occlusion. Methods - We included 51 patients ( 24 women, mean age 69.1 +/- 12.4 years) admitted within 6 hours after stroke symptom onset caused by proximal MCA occlusion, as shown by magnetic resonance angiography ( n = 39), intra-arterial angiography ( n = 4), or transcranial duplex sonography ( n = 8). Blood samples were drawn at hospital admission and 8, 12, 16, 20, and 24 hours after symptom onset. Serum S100B concentrations were determined using a fully automated immunoluminometric assay. A malignant course of infarction was defined as the occurrence of clinical signs of cerebral herniation within the first 7 days of treatment or the clinical decision to perform decompressive hemicraniectomy caused by critical space-occupying swelling as detected by repeated neuroimaging. Results - Sixteen patients developed malignant infarction (31%). Beginning with the 12-hour value, mean S100B serum concentrations were significantly higher in patients with a malignant course compared with those without ( 12 hours 1.23 +/- 1.24 versus 0.29 +/- 0.45 mug/L; 16 hours 1.80 +/- 1.65 versus 0.38 +/- 0.53 mug/L; 20 hours 1.90 +/- 1.53 versus 0.44 +/- 0.48 mug/L; and 24 hours 2.41 +/- 1.59 versus 0.57 +/- 0.66 mug/L; all P < 0.001). A 12-hour S100B value > 0.35 mug/L predicted malignant infarction with 0.75 sensitivity and 0.80 specificity. A 24-hour value > 1.03 mug/L provided 0.94 sensitivity and 0.83 specificity. Conclusions - The serum marker S100B can predict a malignant course of infarction in proximal MCA occlusion. This finding may improve the identification and monitoring of patients at particularly high risk for herniation.