Selective serotonin re-uptake inhibitors are used in the treatment of many psychiatric diseases and also diabetic neuropathy. But treatment with these agents may directly interfere with blood glucose levels. Clinical and experimental trials have demonstrated that some of SSRIs have opposite effects on blood glucose levels. The aim of this study was to investigate the acute effect of paroxetine on glucose regulation. BALB/c mice of either sex weighting 20-40 g were used in the experiments. The animals with pre-treatment blood glucose between 60-160 mg dL(-1) were divided into 2 (normoglycemic and glucose tolerance test) groups. The effect of three doses (5-10-20 mg kg(-1)) of paroxetine on blood glucose level and the mechanisms of this effect are studied. Paroxetine decreased blood glucose levels at almost all doses and times tested in normoglycemic mice and in the intraperitoneal glucose tolerance test. Similar to paroxetine, serotonin (20 mg kg(-1)) also decreased blood glucose levels significantly in both groups. Neither diazoxide (potassium channel opener, 25 mg kg(-1)) nor verapamil (calcium antagonist, 25 mg kg(-1)) could inhibit the hypoglycemic effect of paroxetine. But both methysergide (5-HT(1/2B/2C) antagonist, 1 mg kg(-1)) and ketanserin (5-HT(2A) antagonist, 1 mg kg(-1)) inhibited the decreasing effect of paroxetine and serotonin. In conclusion, paroxetine causes a decrease in blood glucose level probably by an increase in insulin secretion and this increase is provided possibly by intracellular mechanisms mediated by serotonergic receptors and postreceptor events, rather than an influx of calcium from the extracellular medium.