Trends of early expression levels of heat shock protein 70 (Hsp70) and Annexin A1 (ANXA1) in serum of patients with acutely severe traumatic brain injury and the effects on clinical prognosis were investigated. Eighty-four patients with severe traumatic brain injury admitted to Binzhou Center Hospital from June 2014 to July 2017 were selected as the experimental group. Glasgow coma scale and acute physiology and chronic health evaluation II (APACHE II) score were obtained after admission. A further 75 healthy subjects were selected as the control group. Serum expression of Hsp70 and ANXA1 in the two groups was detected by enzyme-linked immunosorbent assay on the 1st, 2nd, 3rd and 4th day after admission. The receiver operating characteristic (ROC) curve was used to analyze the diagnostic value of Hsp70 and ANXA1 for the death of patients with acutely severe traumatic brain injury. Compared with the control group, expression of Hsp70 in the experimental group was significantly increased on the 1st, 2nd, 3rd and 4th day after admission (P