Objective: Atypical antipsychotic drugs have been shown to protect PC12 cells from cell death induced by a variety of stimuli in culture. Recently, it has been postulated that trophic factors, such as brain-derived neurotrophic factor (BDNF), play a role in preventing cell death. It has been shown that antipsychotic drugs attenuate the decrease in rat hippocampal BDNF that results from immobilization-induced stress. We aimed to determine whether the neuroprotective effects of antipsychotic drugs could be mediated through glial cell line–derived neurotrophic factor (GDNF). Methods: We investigated the effects of the atypical antipsychotic drugs quetiapine and clozapine and the typical antipsychotic haloperidol on the secretion of GDNF from rat C6 glioma cells. Results: All 3 drugs increased the amount of GDNF secreted from C6 glioma cells into the medium after 48-hour culture. The intracellular content of GDNF was not altered by treatment with any of the antipsychotic drugs. None of the antipsychotic drugs decreased cell number. Conclusion: This study suggests that stimulation of GDNF release from glial cells by antipsychotic drugs might underlie some of their neuroprotective properties in situ.