To examine its antidiabetic potential in fluoride (F) intoxicated rats, the anti-diabetic drug glibenclamide was administered for 4 weeks to diabetic rats and to diabetic rats exposed to 100 mg NaF/L in the drinking water. In the F treated rats there was a significant reduction in plasma glucose, plasma and hepatic total lipids, cholesterol, triglycerides and plasma low-density lipoproteins (LDL), VLDL- cholesterol, and atherogenic index accompanied by significant increases in HDL- cholesterol, FRAP (ferric reducing ability of plasma) and protein content. Furthermore, significant decreases in SGOT (serum glutamate oxaloacetate transaminase), SGPT (serum glutamate pyruvate transaminase), alkaline and acid phosphatase (ALP and ACP), and glucose-6-phosphatase (G-6-Pase) were observed in these F-treated animals. In addition, administration of the drug decreased hepatic and renal lipid peroxidation with a concomitant increase in total ascorbic acid (TAA), superoxide dismutase (SOD), reduced glutathione (GSH), glutathione peroxidase (GPX), and FRAP levels in the F-treated animals. It is proposed that glibenclamide acts at two levels: (i) at pancreatic islets for increased release of insulin from surviving ? cells, (ii) at the target sites, e.g., hepatic tissue to improve glucose uptake leading to an improvement in the activities of hepatic and renal TAA, SOD, GSH, GPX, and reduction in lipid peroxidation. Glibenclamide may therefore be useful for treatment of diabetes in F endemic areas.