The underlying pathophysiology of polydipsia in schizophrenia is poorly understood. Several studies, however, have suggested that there might be a genetic predisposition to polydipsia. In the present study, using a case-control sample that is independent from the previous family sample, we examined a possible association between polydipsia and functional polymorphisms in the genes of cytochrome P450 (CYP) 1A2 and 2D6, primarily important enzymes to the pharmacokinetics of antipsychotic drugs. Japanese patients with schizophrenia (63 polydipsics and 78 nonpolydipsics) were genotyped for two functional polymorphisms, the 734C/A polymorphism in the CYP1A2 gene and the 2D6*10 allele of the CYP2D6 gene. Neither of the polymorphisms was found to be associated with polydipsia nor was any evidence found that the two polymorphisms have an additive effect on the liability to polydipsia. Our results suggest that the CYP1A2 and CYP2D6 polymorphisms are not likely to play a major role in the development of polydipsia in schizophrenia, although further studies testing other alleles of CYP1A2 and CYP2D6 using different ethnic populations are warranted.