Abstract: OBJECTIVE To investigate the changes of levels of S-100b protein in cerebrospinal fluid (CSF) and serum of patients with intracranial infections after craniotomy and observe the clinical significance so as to provide objective basis for clinical treatment of the infections. METHODS A total of 80 patients with postoperative intracranial infections who underwent the craniotomy from Jan 2013 to Dec 2014 were assigned as the case group, meanwhile, 80 patients without postoperative intracranial infections were chosen as the control group. The levels of S-100b protein, neuronspecific enolase (NSE), C-reactive protein (CRP), procalcitonin (PCT), tumor necrosis factor-α(TNF-α), and nitric oxide in the CSF and serum of the two groups of patients were detected during the acute stage; the levels of S-100b protein in the CSF and serum of the patients in the case group were monitored during the rehabilitation stage. RESULTS The levels of the examination indicators in the CSF and serum were significantly higher in the case group than in the control group during the acute stage; the levels of the S-100b protein in the CSF and serum of the patients in the case group were significantly lower during the rehabilitation stage than during the acute stage; the levels of the S-100b protein in the CSF and serum of the patients with severe infections were significantly higher than those of the patients with mild infections. The multivariate logistic regression analysis showed that the incidence of severe postoperative intracranial infections in the patients undergoing craniotomy was associated with the age, the levels of CRP, PCT, and S-100b protein in the serum and CSF, and there was significant difference (P<0.05). CONCLUSION The craniotomy patients with postoperative intracranial infections are characterized by the elevated levels of the S-100b in CSF and serum during the acute stage, which is closely associated with the illness condition; the levels of the S-100b in CSF and serum can be used as auxiliary indicators for prediction of the progress of the disease and the guidance of clinical treatment.