Severe traumatic brain injury (sTBI) is a serious public health issue with high morbidity and mortality rates. Previous proteomic studies on sTBI have mainly focused on human cerebrospinal fluid and serum, as well as on brain protein changes in murine models. However, human proteomic data in sTBI brain is still needed. We used proteomics and bioinformatics strategies to investigate variations in protein expression in human brains after sTBI, using samples from the Department of Neurosurgery, Affiliated Hospital of Hebei University (Hebei, P.R. China). Our proteomics data identified 4031 proteins, of which 162 proteins were overexpressed and 5 proteins were downregulated. The biological pathways that showed significant changes in protein expression according to bioinformatics analysis were glial cell differentiation, complement activation, apolipoprotein catalysis in statin pathway, and the blood coagulation cascade. Western blot verification of protein changes in a subset of the available tissue samples showed results that were consistent with the proteomics data. This study is one of the first to investigate the whole proteome of human sTBI brains, and provides a characteristic signature and overall landscape of the sTBI brain proteome.