Aim: The purpose of this study was to compare the effect of nateglinide on two-hour post-meal glucose levels with that of glimepiride in patients with type 2 diabetes mellitus. Methods: Glucose and insulin levels were measured during 14-h profiles (comprising three meal challenges) and i.v. glucose tolerance tests performed before and after five-weeks of treatment with nateglinide (120 mg, a.c.) or glimepiride (1 mg, o.d.) in a randomized, two-center, double-blind, crossover study in 26 patients with type 2 diabetes and fasting initial glucose levels < 13.9 mmol/L. Results: Mean two-hour postprandial glucose levels were significantly lower during nateglinide treatment than during glimepiride treatment (9.46 vs. 10.00 mmol/L, resp.; p<0.05). The 14-h incremental glucose area under the curve was -2.2 mmol•h/L during nateglinide treatment and +6.2 mmol•h/L during glimepiride treatment (p<0.01). Nateglinide improved both the early insulin response during meals and the acute insulin response during i.v. glucose tolerance tests, restoring the biphasic insulin secretion pattern. Both insulin secretagogues improved i.v. glucose tolerance relative to the pre-treatment period, but only nateglinide restored a biphasic insulin profile. Conclusions: By restoring a more physiol. post-load insulin response, nateglinide is more effective than glimepiride in controlling postprandial glucose excursions.