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<0.05), while expression of ANXA1 was significantly decreased (P<0.05). Expression levels of serum Hsp70 in the experimental group reached the peak on the 3rd day after admission, and the difference was statistically significant compared with the 1st, 2nd and 4th day (P<0.05). Expression of ANXA1 was the lowest on the 3rd day, and the difference was statistically significant compared with the 1st, 2nd and 4th day (P<0.05). The ROC curve analysis showed that the area under the curve of serum Hsp70 and ANXA1 was, respectively, 0.721 (95% CI: 0.611-0.829) and 0.684 (95% CI: 0.569-0.799). In conclusion, Hsp70 and ANXA1 may be involved in the occurrence and progression of acutely severe traumatic brain injury. The detection of serum Hsp70 and ANXA1 has certain diagnostic value for the death of patients with acutely severe traumatic brain injury.Copyright: © Zhao et al.