Objective To investigate the effects of 4 °C hypertonic saline (HTS) on S100 protein in serum and brain tissues of rats after cardiac arrest (SCA). Method Thirty SD male rats were randomly divided into shame-operated group (A), NS group (B) ,4℃ NS group (C), HTS group (D) and 4℃. HTS group (E), in e-qual number ( n = 6). Drugs were given to the rats of all groups at the initiation of CPR except group A. The rat model of CA was induced by asphyxia. Over 24 hours after restoration of spontanous circulation ( ROSC), venous blood sample was drawn to detcect the concentration of serum S100 protein in each group, and the rats were sacrificed and their brain tissues were taken for comparing the expressions of S100 protein in hippocampus. One-way analysis of variance and q -test were used for comparison among groups. P < 0.05 was considered significant. Results Compared with group A, the concentration of serum S100 protein in other groups were much higher ( P < 0.01). Compared with group B,the concentrations of serum S100 protein in groups C, D and E were also much lower ( P < 0.01). Compared with groups D and E, the concentration of serum S100 protein in group C was much higher ( P < 0.01). Compared with group D, the concentration of serum S100 protein in group D was higher ( P < 0.05). Compared with group A, the expressions of S100 protein in rats brain tissues of groups B,C and D were much higher ( P < 0.01). The expression of S100 protein in brain tissue of rats in group E was also higher than that in rats of group A ( P < 0.05). Compared with group B, the expressions of S100 protein in brain tissues of rats in groups C,D and E were lower (P < 0.05 and P < 0.01). Compared with group C, the expressions of S100 protein in brain tissues of rats in groups D and E were lower (P < 0.01). Compared with group D, the expression of S100 protein in brain tissue of rats in group E was lower (P < 0.05). Conclusions After CA the 4℃ HTS can decrease serum S100 protein level and inhibit the expression of S100 protein in hippocampus, then protecting the brain tissue.