Here we report the gene structure and transcription regulation of the human and mouse G protein-signaling regulator GAIP/RGS19. The GAIP/RGS19 gene is adjacent to and in an opposite orientation to the opioid-receptor-like receptor 1 (ORL1) gene. In both human and mouse, the GAIP/RGS19 gene is composed of seven exons. The first two exons are under the control of two different promoters and are alternatively employed to start the transcription of two 5' distinctive mRNAs. The two promoters appear to compete with and inhibit each other. We have also identified in mice an alternatively spliced short GAIP/RGS19 mRNA that lacks the exon 2 region and utilizes an ATG in exon 3 as its translation initiation codon. As a result, the short GAIP/RGS19 protein does not have the N-terminal 22 amino acid residues of a full-length isoform. GAIP/RGS19 alternative splicing patterns are differentially expressed in various tissues. The mRNA alternative splicing to produce multiple isoforms may play a significant role in regulating the function and selectivity of GAIP/RGS19.