Background: S-100B protein is an established serum marker of primary and secondary brain damage in head injury and stroke. Despite major progress in neurophysiologic monitoring, there are still difficulties in the early identification and quantification of evolving edema or trauma after craniotomy for tumor. In this study we aimed to correlate serum S-100B values with early postoperative neurologic course as well as late outcome in meningioma surgery. Methods: We enrolled 50 consecutive patients who underwent meningioma resection. Serum S-100B was measured preoperatively and postcraniotomy for 7 consecutive days. Twenty-five patients (50%) developed immediate postoperative neurologic deterioration, and 15 (30%) had unfavorable 6-month outcomes. We used the Mann-Whitney U-test to assess the association of S-100B with all variables of interest. We used multiple logistic regression to search for the most significant predictor of postoperative deterioration. Results: Increased S-100B was highly correlated with larger tumors, intraoperative difficulties, postcraniotomy acute deterioration, and long-term poor outcome. In addition, multiple logistic regression showed that age, sex, site, preoperative edema, history of meningioma resection, extent of resection, and histologic type did not correlate with postoperative increases in S-100B. Furthermore, patients with postoperative S-100B values >0.4 μg/L had increased risk of deterioration (relative risk = 9.0; 95% confidence interval, 2.4-34; P <0.0001), and of poor ultimate outcome (relative risk = 11; 95% confidence interval, 1.6-77; P = 0.002). Conclusions: After meningioma excision, postcraniotomy increases in serum S-100B appear to be an early indicator of short-term postoperative neurologic deterioration and of a poor longer-term outcome.