Thistudy aimed to observe the protective effects of sufentanil pretreatment on rat cerebral injury during cardiopulmonary bypass [CPB] and to explore the underlying mechanism. Twenty-four male adult Sprague Dawley [SD] rats were divided into 4 groups. Then, the rat CPB model was established. A 14G trocar was inserted into the atrium dextrum. For rats in S1 and S5 groups, sufentanil [1 microgKg [-1] and 5 microgKg [-1] were applied before CPB process. After the operation, rat brain samples were harvested for measurement of the water content of the brains, total calcium in brain tissue and the level of serum S100beta. Compared with the Sham group, the water content and the total calcium of the brain tissue, and the expression of S100beta in serum were significantly increased in the CPB group [P<0.05] . Compared with the CPB group, sufentanil treatment significantly reduced the water content of the brains, the total calcium and S100beta expression [P<0.05] . The blood pressure and heart rate were significantly decreased in groups CPB, S1, and S5 compared with Sham group during CPB. Compared with the Sham group, the levels of pH and blood lactate in other groups were decreased and increased, respectively, in the post-CPB period. During the CPB and post-CPB periods, the hematocrit levels were significantly down-regulated in groups CPB, S1, and S5 compared with Sham group. In conclusion, sufentanil pretreatment was effective in reducing the cerebral injury during CPB. Reduction in calcium overload may be a potential mechanism in such process