Objective To investigate the effects of propofol anesthesia on the expressions of hippocampus protein and it's relationship with the cognitive function of spontaneously hypertensive rats. Methods Forty spontaneously hypertensive rats were randomly divided into the experiment group (n=20) and control group (n=20). The rats of experiment group were given 100 mg/kg of propofol by peritoneal injection for anesthetic induction and the anesthesia was maintained for 3 h by administering half dose of inductive propofol after 1 h and 2 h. The control group was treated by saline with the same procedure and volume as to propofol injection. Five rats in each group were randomly chosen and decapitated at 3 h, 24 h, 72 h, and on 7 d after anesthesia. Hippocampus tissues were immediately removed to an ice-board and subjected to global protein expression profiling based on two-dimensional gel electrophoresis. Spots expressed with more than two-fold changes were cut out for analysis by the MALDI-TOF-MS. The major functions and involved biological processes of differential proteins were analyzed by database retrievals. Results Eighty-four differentially expressed proteins were detected, among which sixty eight proteins were successfully identified by the MALDI-TOF-MS and 47 proteins were determined by retrievals of protein databases after duplicating ones were removed. Most proteins were low expressed and maintained till the 7 d after anesthesia. Many biological processes (involving the energy metabolism, mitochondrial function, protein folding, and vesicle trafficking, etc.) were affected. Conclusion The influence of propofol anesthesia results in multi-dimensional and dynamic changes of hippocampusin of spontaneously hypertensive rats. Differential expressions of some proteins may involve the molecular mechanism of impairing the cognitive function, but its actual effects need further investigation.