The somatostatin receptor 5 (SSTR5) gene is a candidate gene for bipolar affective disorder (BPAD) as well as for other neuropsychiatric disorders. The gene is positioned on chromosome 16p13.3, a region that has been implicated by a few linkage studies to potentially harbor a disease susceptibility gene for BPAD. Recent evidence shows that the dopamine D2 receptor (DRD2) and SSTR5 interact physically to form heterodimers with enhanced functional activity. Brain D2 dopamine receptors are one of the major targets of neuroleptic treatments in psychiatric disorders. In this study we systematically screened the promoter and coding region of the SSTR5 gene for genetic variation that could contribute to the development of neuropsychiatric disorders. Eleven novel single nucleotide polymorphisms (SNPs) were identified including four missense SNPs, Leu48Met, Ala52Val, Pro109Ser and Pro335Leu. We carried out an association study of BPAD using 80 Danish cases and 144 control subjects, and replication analysis using 55 British cases and 88 control subjects. For the Danish population, association was suggested between silent SNP G573A and BPAD (P = 0.008). For the British population we found association to BPAD with missense mutation Leu48Met (P = 0.003) and missense mutation Pro335Leu (P = 0.004). The statistical significance of the association was, however, greatly reduced after correcting for multiple testing. When combining genotypes from Leu48Met and Pro335Leu into haplotypes, association to BPAD was found in the British population (P = 0.0007). This haplotype association was not replicated in the Danish population. Our results may indicate that the SSTR5 gene is involved in the etiology of BPAD or may exist in linkage disequilibrium with a susceptibility gene close to SSTR5. However, given the marginal statistical significance and the potential for false-positive results in association studies with candidate genes, further studies are needed to clarify this hypothesis.