Antipsychotic medications are often used at higher than the recommended dose and sometimes in a combination regimen to treat schizophrenia. However, in general, high-dose therapies have been abandoned in recent clinical studies. In this study, dose reduction of antipsychotic medication was implemented for patients with chronic schizophrenia, most of whom (81%) had been treated with an antipsychotic high-dose polypharmacy regimen consisting of more than 1000 mg/day in total amount. The results show that merely reducing the amount of antipsychotic led to favourable outcome in 23 out of 41 cases (56%), with another 13 cases (32%) showing no change. Dose reduction ended in failure in only five subjects (12%). Overall, the amount as well as the number of antipsychotic medications was significantly reduced from 1984 mg to 812 mg per day (reductions of 59% and from 3.6 to 2.2, respectively; both P<0.0001). The Global Assessment of Functioning scale improved from 30.6 to 37.2, which reached significance (P<0.001). Accordingly, the Severity of Illness improved from 4.7 to 4.2, and was also significant (P<0.01). Dose reduction is an encouraging strategy to consider for those patients with schizophrenia who have chronically been treated with high-dose antipsychotic polypharmacy, even if judged unavoidable in the past.