Effects of a selective serotonin reuptake inhibitor, zimelidine, on plasma glucose was studied in mice. Zimelidine dose-dependently induced hyperglycemia, although it did not change insulin levels. To determine the involvement of the serotonergic system in zimelidine-induced hyperglycemia, effects of the 5-HT depleter p-chlorophenylalanine(pCPA) were examined. pCPA significantly reduced zimelidine-induced hyperglycemia. This suggests that zimelidine-induced hyperglycemia is mediated by the serotonergic system through its 5-HT reuptake inhibition.