AIM To investgate the changes in the expression of CREB and p-CREB in the cortex of ethanol dependent rats. On other hand, the effects of fluoxetine on these changes were also studied. METHODS Ethanol was administered in drinking water at the concentration of 6% V/V, for 28 d. The expression of CREB and p-CREB in the rat cortex were measured by immunohistochemistry methods. RESULTS It was found that chronic ethanol treatment and its withdrawal did not modify the expression of CREB in the rat cortex. However, the levels of p-CREB in the frontal and piriform cortex of rats were significantly decreased during ethanol withdrawal, and respectively decreased 57.28%?55.84% compared to control rats at 24 h after ethanol withdrawal. When fluoxetine (ip, 10 mg?kg -1) were administried concurrently with ethanol, it can significantly dampen alcohol withdrawal symptoms and antagonize the down-regulation of the phosphorylation of CREB in the frontal and piriform cortex of rats at 24 h after ethanol withdrawal, the expression of p-CREB protein respectively increased 292 58%,128 44% compared with rats intaking ethanol. CONCLUSION CREB may be one of the substance of the signal transduction process for ethanol dependence. Fluoxetine can reverse the decreased p-CREB levels in rat cortex induced by ethanol withdrawal, which may be the part reason of fluoxetine dampening alcohol withdrawal symptoms.