Long-acting depot neuroleptics are likely to receive increasing consideration in the maintenance treatment of schizophrenia because of the growing recognition of noncompliance with daily oral medication in this patient population. The impending availability of haloperidol decanoate in the United States may also increase the use of long-acting neuroleptics. The long-term safety of these drugs, therefore, deserves close scrutiny. Based on experiences with other depot neuroleptics, the safety profile of haloperidol decanoate is unlikely to differ from short-acting formulations of haloperidol. In general, tardive dyskinesia remains the most troubling problem associated with long-term neuroleptic treatment. The available information indicates that all neuroleptics, including long-acting preparations, share the same propensity for causing tardive dyskinesia. Furthermore, the use of the lowest effective dose of a neuroleptic appears to minimize the severity of tardive dyskinesia should it develop. Extrapyramidal symptoms, notably akinesia and akathisia, are also potential concerns of maintenance treatment with oral and depot neuroleptics; however, the occurrence of these side effects appears dose related. Thus, the clinician can favorably influence the benefit-to-risk ratio of long-acting depot neuroleptics by minimizing potential side effects through the use of a low dose strategy.