1. The concentration of serum malondialdehyde (MDA) was measured as the index of lipid peroxidation in female epileptics with phenytoin (PHT) monotherapy. Sera from 20 female epileptics with PHT monotherapy, 12 female epileptics without anticonvulsant therapy and 20 female healthy controls were sampled. The levels of serum copper (S-Cu), serum zinc (S-Zn), copper/zinc superoxide dismutase (CuZn-SOD), and reduced glutathione (GSH) were analyzed as interactive factors of the oxidative stress. 2. For the female epileptics with PHT monotherapy, serum MDA concentration (2.6 +/- 0.7 microM vs control 1.8 +/- 0.6 microM, P < 0.05), CuZn-SOD activity (178.2 +/- 63.5 U/dL vs control 97/1 +/- 36.4 U/dL, P < 0.01), and S-Cu content (126.2 +/- 36.1 micrograms/dL vs control 98.4 +/- 16.7 micrograms/dL, P < 0.05) were significantly increased, but GSH level (27.5 +/- 6.8 microM vs control 32.2 +/- 5.7 microM, P < 0.05) was significantly decreased. The level of serum MDA was associated with the elevation of CuZn-SOD activity (r = 0.54, P < 0.05) and S-Cu content (r = 0.44, P < 0.05) in all the samples collected from epileptics and controls. However, there were no significant differences in all the above parameters between the female epileptics without anticonvulsant therapy and healthy controls. 3. These results indicated that oxidative stress was enhanced in the female epileptics with PHT-monotherapy. Apart from the reactive PHT intermediate, the abnormal metabolism of S-Cu, CuZn-SOD, and GSH was highly involved in the PHT-mediated toxicity. Supplement of GSH, modification of CuZn-SOD enzyme activity and reduction of the absorption of copper may prevent the incidence of fetal hydantoin syndrome during pregnancy.