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Background Previous molecular and genetic studies have implicated RGS4 (regulator of G protein signaling 4) in schizophrenia (SCZ) and bipolar disorder (BPD), but the role of RGS4 in the pathology of the two disorders remains controversial. Recently we identified five different RGS4 splice variants in the human brain. In this study we tested whether expression of specific RGS4 splice variants is altered in the prefrontal cortex of schizophrenic and BPD subjects. Methods Quantitative real-time polymerase chain reaction was used to detect overall RGS4 expression and the messenger RNA levels of the four RGS4 splice variants in the prefrontal cortex of schizophrenic ( n = 27), BPD ( n = 27), and normal ( n = 27) subjects. Results Compared with the normal group, the expression of a specific splice variant RGS4-3 was decreased in the dorsolateral prefrontal cortex of the SCZ group, whereas overall RGS4 expression and expression of other RGS4 isoforms did not differ significantly between the control and SCZ groups. The messenger RNA levels of RGS4 isoforms did not change between the control group and the BPD group. Conclusions Our results suggest the possibility that alterations in the expression of RGS4-3 contribute to the development of SCZ.