Background-The results of early conventional tests do not correlate with cerebral outcome after cardiac arrest. We investigated the serum levels of astroglial protein S-100 as an early marker of brain damage and outcome after cardiac arrest. Methods and Results-In 66 patients undergoing cardiopulmonary resuscitation after nontraumatic cardiac arrest, blood samples for the evaluation of S-100 were drawn immediately after and 15, 30, 45, and 60 minutes; 2, 8, 24, 48, and 72 hours; and 7 days after initiation of cardiopulmonary resuscitation. Moreover, the serum levels of neuron-specific enolase were determined between 2 hours and 7 days. If patients survived for Ͼ48 hours, brain damage was assessed by a combination of neurological, cranial CT, and electrophysiological examinations. Overall, 343 blood samples were taken for the determination of S-100. Maximum S-100 levels within 2 hours after cardiac arrest were significantly higher in patients with documented brain damage (survivors and nonsurvivors, 3.70Ϯ0.77 g/L) than in patients without brain damage (0.90Ϯ0.29 g/L). Significant differences between these 2 groups were observed from 30 minutes until 7 days after cardiac arrest. In addition, the positive predictive value of the S-100 test at 24 hours for fatal outcome within 14 days was 87%, and the negative predictive value was 100% (PϽ0.001). With regard to neuron-specific enolase, significant differences between patients with documented brain damage and those with no brain damage were found at 24, 48, and 72 hours and 7 days. Conclusions-Astroglial protein S-100 is an early and sensitive marker of hypoxic brain damage and short-term outcome after cardiac arrest in humans.