Decreasing oxidative stress and increasing antioxidant defense has been hypothesized as one mechanism by which caloric restriction (CR) increases longevity in animals. A total of 46 moderately overweight volunteers (BMI: 25-30 kg/m2), ages 20-42 yr were randomized to either high glycemic (HG) or low glycemic (LG) dietary load CR regimen at either 10% (n=12) or 30% (n=34) of basal caloric intake. All food was provided to participants for 6 mo. Overall, after controlling for CR levels and dietary regimen for 6 mo, plasma glutathione peroxidase activity increased (p=0.04) and plasma protein carbonyl levels decreased (p=0.02) and a non-significant decrease in plasma 8-epi-prostaglandin F2α level was observed (p=0.09). No significant change was observed in other plasma antioxidants such as superoxide dismutase and catalase. These findings indicate that short term CR (10% or 30%) in moderately overweight subjects modulates some but not all measures of antioxidant defense and oxidative stress.