Oxidative stress is increased postprandially and during long-term hyperglycemia in type 2 diabetic patients who present with poor response to glibenclamide. This study was designed to evaluate the effects of the antioxidant flavonoid silymarin in improving long-term and postprandial glycemic and weight control in type 2 diabetic patients treated with glibenclamide. Using a randomized, double-blind, placebo-controlled design, 59 type 2 diabetic patients, previously maintained on 10 mg/day glibenclamide and diet control, with poor glycemic control, were randomized into three groups: the first two groups were treated with either 200 mg/day silymarin or placebo as adjuncts to glibenclamide, and the third group was maintained on glibenclamide alone for 120 days. Fasting and 4-hour postprandial plasma glucose, glycated hemoglobin (HbA(1c)), and body mass index (BMI) were evaluated at baseline and after 120 days. Compared with placebo, silymarin treatment significantly reduced both fasting and postprandial plasma glucose excursions, in addition to significantly reducing HbA(1c) levels and BMI after 120 days. No significantly different effects were observed for placebo compared to glibenclamide alone. In conclusion, adjunct use of silymarin with glibenclamide improves the glycemic control targeted by glibenclamide, during both fasting and postprandially, an effect that may be related to increased insulin sensitivity in peripheral tissues.