Although minimally invasive neurosurgical techniques are highly sophisticated nowadays, almost any operative procedure causes an inevitable surgical trauma to the brain. As a consequence unfavorable functional outcomes are not rare. Intraoperative biochemical monitoring can be helpful first to detect but also to prevent brain damage. We investigated if serum S-100 protein (S-100) levels are a reliable marker for the extent of acute cerebral damage caused by surgical trauma or postoperative complication. S-100 is present in the cytosol of glial cells. This protein leaks into the extracellular space after cell damage and can be detected both in the cerebrospinal fluid (CSF) and serum. To determine S-100 protein levels, serum samples from 20 patients with various intracranial tumors were collected before surgery, and at one day, as well as at seven days after surgery. It was hypothesised that the size of the tumor-brain contact surface (TBCS) was closely related to the dimension of the surgical trauma. TBCS was measured from radiological imaging. The pre- and postoperative (day 1 and day 7) clinical condition of each patient was assessed. The S-100 levels were correlated with the TBCS and the clinical condition. Levels of S-100 on day 1 and day 7 were significantly higher as compared with levels on day 0 ( p = 0.02, respectively p = 0.01). There was a significant relationship between rise of S-100 level and worsening of clinical condition between day 0 and day 1 ( p = 0.001). Also a significant positive relationship between TBCS and the level of S-100 could be found on day 1 and on day 7 ( R = 0.71, p = 0.0009, respectively R = 0.73, p = 0.004). Furthermore, a significant relationship between the rise of S-100 level between day 0 and day 1, as well as between day 0 and day 7, and TBCS could be documented ( R = 0.61, p = 0.01, respectively R = 0.64, p = 0.005). In conclusion, serum S-100 levels are a reliable marker for acute or recent CNS damage caused by neurosurgical manipulation or as a result of secondary postoperative complications. Therefore, intraoperative monitoring of serum S-100 levels seems very promising. In such a setting the negative effects of surgical manipulation can be measured instantaneously, which should bring the neurosurgeon to change his strategy. As a consequence the surgical trauma can be minimized and functional outcome can be optimized.