Free radicals have been implicated in beta-cell destruction. pancreatic antioxidant enzymatic defenses provide significant endogenous protection from these highly cytotoxic effector molecules. In our colony of BB rats, the reliability of peripheral blood lymphocyte count (PBLC) as a predictor of diabetes onset was assessed in 99 male and 110 female BB rats. In rats with a PBLC < 4,200 mm3, 90% of males and 86% of females developed diabetes by 120 days of age and are designated "lymphopenic" or BBL. Rats with a PBLC > 4,200 mm3 have a much lower incidence of insulin-dependent diabetes mellitus (IDDM) and are designated "nonlymphopenic" or BBNL. In separate cohorts of normoglycemic (prediabetic) BBL rats (high risk for developing diabetes) and BBNL rats (low risk for developing diabetes), the activities of pancreatic cytosolic antioxidant enzymes, copper-zinc superoxide dismutase (CuZnSOD), catalase (CAT), and glutathione peroxidase (GPX) were determined. Alterations in CuZnSOD and CAT were noted in BBL males only as compared to BBNL males and BBL and BBNL females. CuZnSOD and CAT activities were significantly lower in BBL males. GPX showed a similar trend. The changes in pancreatic antioxidant enzymes precede overt hyperglycemia in male rats at risk for development of diabetes and may result in increased beta-cell vulnerability to oxygen-derived free radical destruction.