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Oxidative stress resulting from enhanced free-radical formation and/or a defect in antioxidant defenses has been implicated in the pathogenesis of experimental diabetic neuropathy. The objective of this study was to evaluate plasma levels of various biomarkers of oxidative stress in diabetic subjects in relation to the presence or absence of polyneuropathy (PN) and/or cardiovascular autonomic neuropathy (CAN).Plasma 8-iso-prostaglandin F2α (8-iso-PGF2α), superoxide anion (O2•−) generation, lag phase to peroxidation by peroxynitrite (ONOO−), vitamin E-to-lipid ratio, and vitamin C were measured in nonsmoking diabetic patients without PN and CAN (PN−/CAN− group; n = 62), in a group with PN but without CAN (PN+/CAN− group; n = 105), in those with both PN and CAN (PN+/CAN+ group; n = 22), and in healthy control subjects (n = 85).All three markers of oxidative stress were significantly increased, and both markers of antioxidant defense were decreased in the PN+/CAN− group compared with the control group (all P < 0.05). PN−/CAN− subjects showed a significant increase compared with control subjects for 8-iso-PGF2α, O2•−, and ONOO− and a decrease for the vitamin E-to-lipid ratio (all P < 0.05). In the PN+/CAN− group, a significant increase compared with the PN−/CAN− group was noted for O2•−, whereas the vitamin E-to-lipid ratio and vitamin C were reduced (all P < 0.05). No significant differences were noted between the PN+/CAN− and PN+/CAN+ groups for each of the five markers of oxidative stress. In multivariate models, O2•− and ONOO− were independently associated with neuropathic deficits, but diabetes duration and triglyceride levels were also independent determinants.Oxidative stress is enhanced in diabetic patients before the development of PN but to an even higher degree in those with PN, without further significant increase in relation to superimposed autonomic neuropathy. However, apart from oxidative stress, diabetes duration and triglyceride levels are also related to the severity of PN.