Background and Purpose Better techniques are needed to monitor infarction volume and predict neurological outcome after ischemic brain infarction. We evaluated the usefulness of serial measurements of S-100 protein versus neuron-specific enolase (NSE) in blood samples from patients with acute stroke. Methods Using nonisotopic sandwich immunoassays, we measured plasma concentrations of S-100 protein and NSE on admission and on days 3, 4, 7, and 14 after infarction in 44 patients (age range, 22 to 86 years; mean age, 65.1 years; 12 female, 32 male). Infarct volume was measured by volumetric CT on day 4 after ictus, and clinical outcome was assessed at discharge from hospital with the Activities of Daily Living Scale and 6 months after infarction with the Glasgow Outcome Scale. Results Peak blood levels of S-100 protein were found on day 2.5+/-1.3, and peak levels of NSE were found on day 1.9+/-0.8 after infarction. Peak plasma levels of S-100 protein correlated well with infarct volume (r=.75, P<.001) and with clinical outcome assessed with the Glasgow Outcome Scale (r=.51, P<.001). Serum levels of NSE correlated with infarct volume (r=.37, P<.05) but not with clinical outcome (r=.18, P>.05). Conclusions The results of our study indicate that measuring blood concentrations of S-100 protein periodically in the first 10 days after cerebral infarction helps to predict infarct volume and the long-term neurological outcome more accurately than periodic measurements of blood concentrations of NSE.