Neuroleptic-induced orofacial dyskinesia is a putative animal model of tardive dyskinesia (TD) whose pathophysiology has been related to free radical generation. In accordance with this, literature data indicate that neuroleptic administration can increase the turnover of dopamine and, consequently, the production of reactive substances as products of its metabolism. Recent studies from our laboratory have indicated that diphenyl diselenide, a organic selenium compound with thiol-peroxidase-like activity, present neuroprotective effects in vitro and in vivo models. The aim of the present study was to evaluate the effects of diphenyl diselenide in a chronic model of orofacial dyskinesia induced by fluphenazine. Fluphenazine enantate was administered (21 mg/kg; I.M.) each 21days for a period of 6 months to rats treated concomitantly with diphenyl diselenide (1 mg/Kg; s.c.) three times a week. Fluphenazine caused a significant increase (p<0.05) in vacuous chewing movements (VCM) that was observed in 85% of rats. Diphenyl diselenide decreased this value to 50% in rats receiving fluphenazine plus diphenyl diselenide (Low VCM). Furthemore, fluphenazine caused a significant reduction in body weight gain with p<0.05. [³H] dopamine uptake was measured in slices of striatum. There was a significant decrease in [³H] dopamine uptake in rats treated with fluphenazine in relation to control group and similarly in high VCM rats treated with both drugs. However, the rats treated with both drugs and that did not develop orofacial dyskinesia (Low VCM), showed a significant (p<0.05) increase in [³H] dopamine uptake. The present results suggest that diphenyl diselenide could interact with neurotransmiter systems causing a neuroprotective effect that was evidenced by a significant reduction in percentage of rats that developed orofacial dyskinesia.