Regulators of G-protein signaling are a family of proteins that negatively regulate the intracellular signaling of G protein-coupled receptors, such as the serotonin receptor. Recent studies have suggested that one of these proteins, the regulator of G-protein signaling 2 (RGS2), plays an important part in anxiety and/or aggressive behavior. To explore the involvement of the RGS2 gene in the vulnerability to suicide, we screened Japanese suicide victims for sequence variations in the RGS2 gene and carried out an association study of RGS2 gene polymorphisms with suicide victims. In the eight identified polymorphisms that were identified by mutation screening, we genotyped four common single-nucleotide polymorphisms (SNPs) in the RGS2 gene, and found significant differences in the distribution of the SNP3 (C+2971G, rs4606) genotypes and alleles of the SNP2 (C-395G, rs2746072) and the SNP3 between completed suicides and the controls. The distribution of the haplotype was also significantly different between the two groups (global p<0.0001). Furthermore, RGS2 immunoreactivity significantly increased in the amygdala and the prefrontal cortex (Brodmann area 9 (BA9)) of the postmortem brain of the suicide subjects. These findings suggest that RGS2 is genetically involved in the biological susceptibility to suicide in the Japanese population.