Several serotonin (5-HT) receptor antagonists with varying specificities for the 5-HT receptor types, were studied with regard to their effects on blood glucose levels in mice. The non-selective antagonists, metergoline and methysergide, proved to be hyperglycemic at doses commonly used to antagonize 5-HT receptors. In contrast, ritanserin (a 5-HT₂ and 5-HT_1c antagonist) and MDL 72222 (a 5-HT₃ antagonist) were effective only at doses which surpassed the dose range considerd to be selective for their respective receptors. The results suggest that 5-HT systems play a role in maintaining glucose homeostasis and that 5-HT₁ receptors may be particularly important in this function. Furthermore, the inherent hyperglycemic properties of non-selective serotonin antagonists described here, are pertinent to studies using these agents to investigate glucose metabolism.