The present study examined the effect of chronic fluoxetine administration on the feeding behavior of fructose-fed rats. Male fructose-fed rats were divided into two groups: (1) control fructose-fed rats (CFR), and (2) fructose-fed rats treated with oral fluoxetine 5 mg/kg/day for 30 days (FFR). The feeding behaviors and plasma glucose levels in response to either serotonin (5-HT, 5 mg/kg) or saline injection were studied. The results showed 5-HT increased CFR plasma glucose in a dose-dependent fashion while FFR demonstrated significantly lower responses to 5-HT stimulation. 5-HT significantly increased the feeding latency and decreased the amount of food intake in the CFR. Fluoxetine treatment did not affect the 5-HT effect on food intake amount but significantly reduced the 5-HT effect on feeding latency. Putting the animals in a new environment increased the 5-HT effect on feeding latency further; the effect was ameliorated in the FFR. In conclusion, 5-HT induced hyperglycemia, increased feeding latency and decreased food intake amount in fructose-fed rats. Chronic administration of fluoxetine counteracted the 5-HT effects on blood glucose level and feeding latency, but not on the amount of food intake.