Tissue accumulation of advanced glycation end products (AGEs) has been implicated in the oxidant-induced vascular pathology of diabetes and other diseases. Homozygous sickle cell anemia (SCA) is a state of oxidative stress caused by an imbalance between pro-oxidant and antioxidant factors. We tested the hypothesis that plasma AGE (PAGE) levels are higher in SCA patients with reduced endogenous antioxidant capacity. Blood was obtained from 48 age- and race-matched children attending sickle cell or outpatient clinics. The subjects were classified as either SCA in steady state (n = 25) or non-sickle cell controls (n = 23). PAGE levels were measured by chemiluminescent immunoassay using an anti-AGE antibody (6D12). Reduced (GSH) and oxidized (GSSG) glutathione were measured by capillary zone electrophoresis. Results (means ± SEM) showed that PAGE levels (arbitrary units/mg total protein) were significantly higher (p < .01) in SCA patients (3022 ± 313) compared to controls (1990 ± 182). Erythrocyte GSH and GSSG (μmol/L RBC) were not significantly different between groups. In contrast, whole blood GSH and GSSG (μmol/L blood) were significantly lower (p < .01) in SCA patients (451 ± 158; 25.8 ± 4.4) compared to controls (673 ± 117; 54.4 ± 7.5). Whole blood GSH was inversely correlated with PAGE in both SCA patients (y = -6.1 × +5632, r = -.70, p < .01) and controls (y = -4.1 × + 4756, r = -.55; p < .01). Higher circulating AGE levels in SCA patients suggest that AGEs may play a role in the vascular pathology of SCA similar to that reported in diabetes. The inverse relationship between PAGE and GSH levels suggests that AGE synthesis is higher in subjects with low endogenous antioxidant capacity. These results provide biochemical rationale for reports that antioxidant therapy is beneficial in the clinical management of SCA patients and suggest that supplementation may be more beneficial in the subset of patients with low endogenous antioxidant capacity.