An open-label prospective cross-over trial was performed to compare the efficacy and safety of once daily low-dose gliclazide (20 mg/day) with that of nateglinide at the usual dosage (270 mg/day, 90 mg t.i.d.) in Japanese type 2 diabetics with relatively good glycemic control (HbA1c<7.0%). Eight patients received 20 mg/day of gliclazide and 16 received 270 mg/day of nateglinide. After at least 12 weeks of gliclazide or nateglinide therapy, the drugs were switched and treatment was continued for another 12 weeks. The final HbA1c value was modestly, but significantly, lower after gliclazide treatment than after nateglinide treatment (6.2% vs. 6.4%). However, symptoms related to hypoglycemia were significantly more common with gliclazide treatment than nateglinide treatment (7 vs. 0 cases), although there were no severe hypoglycemic events. While gliclazide acts as a free radical scavenger, there was no effect on parameters of oxidative stress such as malondialdehyde-modified low density lipoprotein and thiobarbituric acid-reactive substances at the low dosage tested. In conclusion, both drugs are reasonable options for early type 2 diabetes. Compared with the regular dose of nateglinide, 20 mg/day of gliclazide achieved modestly better glycemic control with an increased frequency of hypoglycemia in diabetic patients with relatively good glycemic control.