OBJECTIVE: To evaluate the safety and effectiveness of tetrabenazine for the treatment of tardive dyskinesia. DATA SOURCES: Literature was accessed through MEDLINE (1966-September 2010) and The Cochrane Library using the terms tetrabenazine, tardive dyskinesia, and movement disorders. In addition, references from publications identified were reviewed. STUDY SELECTION AND DATA EXTRACTION: All English-language articles identified from the data sources were reviewed. DATA SYNTHESIS: Options available for the management of tardive dyskinesia are limited. Tetrabenazine is a central monoamine-depleting agent approved by the Food and Drug Administration for chorea associated with Huntington's disease. Three prospective studies of tetrabenazine in the treatment of tardive dyskinesia were identified, as well as 8 additional trials, 1 case series, and 8 case reports. Tetrabenazine may provide benefit in managing symptoms of tardive dyskinesia unresponsive to other treatment modalities. Treatment of tardive dyskinesia with tetrabenazine may be limited by cost and clinically significant adverse effects such as depression, parkinsonism, and somnolence. CONCLUSIONS: Small trials indicate tetrabenazine may be effective for the treatment of tardive dyskinesia. However, larger, well-conducted trials are needed to confirm these findings. Currently, there is a lack of data coupled with the risk of significant adverse effects to recommend the routine use of tetrabenazine in the management of tardive dyskinesia. Before using tetrabenazine for the management of tardive dyskinesia, all other options should be exhausted and careful monitoring employed.