The main objective of this study was to assess the possible oxidative damage caused by a chronic exposure to fluphenazine in animal models and the protective effect of diphenyl diselenide. The treatments were performed in 6 months. Animals were divided into fluphenazine (25mg/Kg, i.m.), diphenyl diselenide (1mg/Kg, s.c.), fluphenazine plus dipheny diselenide and control groups. Parameters of oxidative damage were assessed in hepatic and renal tissue. Long-term treatment with fluphenazine caused an increase in TBARS levels in liver and kidney homogenates. Diphenyl diselenide treatment did not affect d-aminolevulinate dehydratase (d-ALA-D) activity but fluphenazine alone or in combination with diphenyl diselenide showed an inhibitory effect on d-ALA-D activity in liver. The interaction between diphenyl diselenide and fluphenazine increased the reactivation index of hepatic d-ALA-D by 40%. Superoxide dismutase (SOD) activity was decreased in the liver of rats treated with fluphenazine alone. The association between fluphenazine and the diphenyl diselenide was able to recuperate the SOD activity in the liver of rats. In kidney of rats treated with fluphenazine plus diphenyl diselenide presented an inhibition in SOD activity. Finally, catalase (CAT) activity was augmented in liver from rats treated with fluphenazine and this increase was not observed when diphenyl diselenide was co-administrated. Taken together, these results indicate that the association of organoselenium compounds with fluphenazine could protect the liver from TBARS and recovery the SOD and CAT activity of the inhibition caused by the fluphenazine.