Haloperidol is a commonly used, typical, antipsychotic drug (APD) that acts strongly against positive symptoms, but has fewer therapeutic effects on, or may even aggravate, negative symptoms and cognitive deficits in patients with schizophrenia. Loss of oligodendrocytes has been suggested as a factor associated with the negative symptoms of schizophrenia. Recent study shows that chronic haloperidol treatment induced down-regulation of oligodendrocyte-related genes in certain brain regions of mouse. In this study, we used primary oligodendrocyte progenitor cell cultures from 1- to 3-day-postnatal rats to investigate the direct effects of haloperidol on the proliferation and differentiation of oligodendrocyte progenitor cells. Our results showed that (i) haloperidol (0-10.0 micromol.L-1) facilitated the proliferation of oligodendrocyte progenitor cells, (ii) chronic haloperidol (0.5 micromol.L-1) treatment decreased the number of myelin basic protein positive oligodendrocytes and reduced the oligodendrocytes cells possessing myelin-like membranes, resulting in inhibition of the terminal differentiation of oligodendrocytes, and (iii) D3 receptor mRNA was detected in oligodendrocyte progenitor cells, and haloperidol treatment induced a down-regulation of D3 receptor mRNA. These results suggest that the typical antipsychotic drug haloperidol affects the development of oligodendrocyte progenitor cells, and that D3 receptor down regulation may be involved. Our observations provide new insight into possible cellular mechanisms responsible for the side effects of typical antipsychotic drugs and support the concept that abnormality of oligodendrocytes may be involved in the pathogenesis of schizophrenia.