An accumulating body of evidences point to the significance of neuroinflammation and immunogenetics in schizophrenia, characterized by increased serum concentration of several pro-inflammatory cytokines. In the central nervous system (CNS), the microglial cells are the major immunocompetent cells which release pro-inflammatory cytokines, nitric oxide (NO) and reactive oxygen species to mediate the inflammatory process. In the present study, we investigated whether or not atypical antipsychotics, namely perospirone, quetiapine and ziprasidone, would have anti-inflammatory effects on the activated microglia which may potentiate neuroprotection. All three atypical antipsychotics significantly inhibited NO generation from activated microglia while perospirone and quetiapine significantly inhibited the TNF-alpha release from activated microglia. Antipsychotics, especially perospirone and quetiapine may have an anti-inflammatory effect via the inhibition of microglial activation, which is not only directly toxic to neurons but also has an inhibitory effect on neurogenesis and oligodendrogenesis, both of which have been reported to play a crucial role in the pathology of schizophrenia.