Fed and 24 h fasted rats were treated by stomach tube with different doses of tolbutamide or glypentide, and they were compared with controls treated with placebo. At low doses glypentide was 10 times more effective as hypoglycemic agent than tolbutamide, whereas it was only twice as effective in the fasted rats. Supramaximal doses of either drug produced the same effect decreasing blood glucose levels. Both drugs were able to decrease rise of blood ketones in fasted rats, but the comparative effect was not parallel to the one observed on glycemia and not proportional to the doses used. Different responses are interpreted as a function of the hypoglycemic effect which is mainly mediated through the insulinotropic action of these drugs, while the hypoketonemic is the result of their insulinotropic effect and direct action on lipolysis and ketogenesis.