Background: Chronic obstructive pulmonary disease (COPD) is a common cause of death and disability worldwide. Brain hypoxia due to acute COPD exacerbation or in chronic course of disease can affect the central nervous system and lead to behavioral and cognitive dysfunction. In addition, hypoxia causes brain injury which increases the serum biomarker of S100B protein excreted from astrocytes. The aim of the study was to assess the effect of hypoxia following COPD exacerbation on the brain by measuring the S100B. Methods: Our study consisted of group of COPD patients. These groups had 80 peoples. The serum S100B protein levels of COPD patients who were admitted to the emergency department of a teaching Hospital were measured by the ELISA method, and their correlation with other clinical and laboratory parameters was assessed. Statistical methods consisted of mean ± standard deviation. We assessed the association between two categorical variables of S100B and presence or absence of COPD by Chi-squared test. We used SPSS version 21 with p<0.05 considered significant. Results: Out of 80 COPD exacerbation patients, 39 (48.8%) were men. The mean age of the patients was 66 ± 12.76 years (range, 30–87). S100B protein was positive in 35 (43.8%) and negative in 45 (56.2%) patients. There were no significant correlations between S100B and other parameters, such as PH, O2 Saturation, bicarbonate, and clinical findings such as respiratory rate, pulse rate and blood pressure, except for carbon dioxide in arterial blood (PaCO2) (p=0.046). Conclusion: Serum S100B protein was higher in acute COPD exacerbation patients and could be a marker of brain injury.