Insulin-dependent diabetes mellitus (IDDM) is a chronic disorder that results from autoimmune destruction of the pancreatic beta-cells. Recent evidence suggests that oxidative damage, resulting from both cytokine-induced production of toxic free radicals and low antioxidant capacity of the beta-cell plays a significant role in the pathogenesis of IDDM. Islet cell antibodies (ICA) have been the best validated marker of risk for the development of IDDM in predisposed individuals, i.e. first-degree relatives of patients with IDDM. We investigated the total plasma antioxidant status (TAS) in both ICA-positive and ICA-negative first-degree relatives of patients with IDDM, to assess the level of overall protection against oxidative damage. TAS was significantly lowered in ICA-positive when compared to both ICA-negative and healthy subjects (p < 0.001), while no significant difference was found in comparison to recently diagnosed patients with IDDM. TAS values were not significantly influenced by gender, age and smoking habits in all groups, as well as by ICA titers in the group of ICA-positive subjects. Results indicate that prediabetic condition, apart from well-established immunological and metabolic alterations, could be associated with biochemical changes revealing complex disturbances of the antioxidative defence system. Although TAS is a functional rather than specific marker, its measurement is likely to be a valuable tool for understanding the mechanisms of specific beta-cell injury.