RGS4 (regulator of G protein signaling 4) protein is a GTPase-activating protein specific for Gi/o and Gq alpha subunits. It is highly expressed in brain but the mechanisms by which RGS4 expression is regulated remain unknown. RGS4 is associated with schizophrenia either through heritable genetic polymorphisms or as a co-regulated mediator of the pathology, and may play a role in other brain diseases. As a necessary step towards understanding the transcriptional regulation of RGS4, we isolated full-length splice variants of the human RGS4 and mouse Rgs4 gene using bioinformatic predictions, followed by RACE, RT-PCR, and sequencing. In human brain, we found five different isoforms RGS4-1, RGS4-2, RGS4-3, RGS4-4 and RGS4-5 of which RGS4-2, RGS4-3, RGS4-4 and RGS4-5 are novel. RGS4-1 and 2 encode a 205-amino acid protein, while RGS4-3 encodes a 302 aa protein with an N-terminal extension. RGS4-4 and RGS4-5 encode truncated proteins of 93 aa and 187 aa respectively. Our results indicate that RGS4-1, RGS4-2, RGS4-3 and RGS4-4 are translated into proteins. In contrast, the mouse brain has 3 different splice variants, Rgs4-1, Rgs4-2 and Rgs4-3 which encode the same 205 aa protein but vary in their 3'UTRs. Among the mouse isoforms, Rgs4-1 and Rgs4-3 are novel. Human RGS4 has four different transcription start sites and three different stop sites. We found differential expression of the human isoforms in dorsolateral prefrontal and visual cortex. All five RGS4 splice variants are expressed at high levels in human cortical areas although RGS4 isoforms 1, 2, and 3 are not expressed in the cerebellum. RGS4-2 is tissue-specific whereas RGS4-4 and RGS4-5 appear to be ubiquitously expressed. Our results suggest the intriguing possibility that RGS4 gene expression in the human brain is spatially and temporally regulated through differential transcription of isoforms from alternative promoters. This may have implications for the physiological role of RGS4 and in pathologies of the brain.