Procyanidins, a group of flavonoids, are oligomeric forms of catechins that are abundant in red wine, grapes, cocoa, and apples. Paraoxonase acts as an antioxidant enzyme and protects low-density lipoprotein-cholesterol against oxidation. In our study we aimed to evaluate the effects of grape seed extract (GSE) on paraoxonase activities in streptozotocin-induced diabetic rats. Our study included four groups of rats: Group I (n=8), control; Group II (n=10), GSE-supplemented; Group III (n=6), streptozotocin-induced diabetic; and Group IV (n=7), GSE-supplemented diabetic rats. Serum paraoxonase activities were determined with a spectrophotometric method. Paraoxonase activities in Group III were significantly lower than in the other three groups (P<.001, P<.001, and P=.005 for Groups I, II, and IV, respectively), and Group IV showed increased paraoxonase activities compared to Group III (P=.005). This is the first study to show an association between paraoxonase status and GSE supplementation and demonstrated that GSE increased paraoxonase activities. This beneficial effect of GSE was more obvious in the diabetic group, which was more prone to atherosclerotic events compared to the healthy population.