GPR50 is an orphan G protein-coupled receptor (GPCR) located on Xq28, a region previously implicated in multiple genetic studies of bipolar affective disorder (BPAD). Allele frequencies of three polymorphisms in GPR50 were compared in case-control studies between subjects with BPAD (264), major depressive disorder (MDD) (226), or schizophrenia (SCZ) (263) and ethnically matched controls (562). Significant associations were found between an insertion/deletion polymorphism in exon 2 and both BPAD (P = 0.0070), and MDD (P = 0.011) with increased risk associated with the deletion variant (GPR50 Δ502-505). When the analysis was restricted to female subjects, the associations with BPAD and MDD increased in significance (P = 0.00023 and P = 0.0064, respectively). Two other single-nucleotide polymorphisms (SNPs) tested within this gene showed associations between: the female MDD group and an SNP in exon 2 (P = 0.0096); and female SCZ and an intronic SNP (P = 0.0014). No association was detected in males with either MDD, BPAD or SCZ. These results suggest that GPR50Δ502-505, or a variant in tight linkage disequilibrium with this polymorphism, is a sex-specific risk factor for susceptibility to bipolar disorder, and that other variants in the gene may be sex-specific risk factors in the development of schizophrenia.