Aims To evaluate the effects of gliclazide on oxidative status and vascular response to systemic administration of L-arginine, the natural precursor of nitric oxide (NO), in Type 2 diabetic patients. Methods Thirty Type 2 diabetic patients received glibenclamide (n = 15) or gliclazide (n = 15) in a 12-week, randomized, observer-blinded, parallel study. Plasma lipid peroxides, total radical-trapping anti-oxidant parameter (TRAP), and blood pressure responses to an intravenous bolus of L-arginine were measured pre- and post-treatment. Results At 12 weeks, gliclazide patients had lower plasma lipid peroxides (13.3 +/- 3.8 mumol/l vs. 19.2 +/- 4.3 mumol/l; P = 0.0001) and higher plasma TRAP (1155.6 +/- 143.0 mumol/l vs. 957.7 +/- 104.3 mumol/l; P = 0.0001) than the glibenclamide patients. Gliclazide but not glibenclamide significantly reduced systolic and diastolic blood pressure (P = 0.0199 and P = 0.00199, respectively, two-way repeated measures analysis of variance) in response to intravenous L-arginine. Conclusions Gliclazide reduces oxidative stress in Type 2 diabetic patients by improving plasma anti-oxidant status. This effect is associated with enhanced NO-mediated vasodilation.