Genetic linkage studies in bipolar disorder (BPD) suggest that a susceptibility locus exists on chromosome 18p11. The metallophosphoesterase (MPPE1) gene maps to this region. Dysregulation of protein phosphorylation and subsequent abnormal cellular signaling has been postulated to be involved in neuropsychiatric disorders thus making MPPE1 a plausible biological candidate gene for BPD. In this study, we hypothesized that genetic variation in the MPPE1 gene contributes to BPD. We tested this hypothesis by genotyping four SNPs (rs871044; rs3974590; rs593713; rs602201) in BPD patients (n = 570) and healthy controls (n = 725). Genotypes and allele frequencies were compared between groups using Chi square contingency analysis. Linkage disequilibrium (LD) between markers was calculated and estimated haplotype frequencies were compared between groups. Single marker analysis revealed an association of rs3974590 with BPD (P = 0.009; permutation corrected P = 0.046). Haplotype analysis did not show any significant association with disease after permutation correction. Our results provide evidence of an association between a polymorphism in the MPPE1 gene and BPD. Additional studies are necessary to confirm and elucidate the role of MPPE1 as a susceptibility gene for BPD on chromosome 18p.