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P-glycoprotein (P-gp), which is coded by the MDR1 gene, in the brain capillary endothelial cell limits the entry of many drugs including antipsychotics into the brain. The aim of this study is to examine whether a functional polymorphism, a C to T substitution at position 3435 in exon 26 of the MDR1 gene, is associated with susceptibility to polydipsia–hyponatremia in schizophrenia (SCZ) in a Japanese case–control sample. It has been reported that individuals homozygous for this polymorphism had significantly lower MDR1 expression levels and dysfunction of MDR1 (PNAS 97:3473–3478, 2000). Furthermore, the brain entry of risperidone and 9-hydroxyrisperidone has been shown to be greatly limited by P-gp (Int J Neuropsychopharmacol 7:415–419, 2004). In order to our knowledge, this is the first association study between the MDR1 polymorphism and polydipsia–hyponatremia in SCZ. Our sample includes 331 patients with SCZ (DSM-IV) (84 with polydipsics and 247 non-polydipsic controls). The common C3435T polymorphism of the MDR1 was genotyped for both groups and differences in genotype and allele frequency between cases and controls were evaluated using the χ2-test. A significant association between the MDR1 C3435T polymorphism and polydipsia was found (χ2 = 4.43, d.f. = 1, P = 0.035; OR = 1.46; 95%CI = 1.03–2.07). Our results suggest that the MDR1 C3435T polymorphism may confer susceptibility to polydipsia in SCZ.