Tyrosine hydroxylase (TH) gene is the ratelimiting enzyme in the synthesis of catecholamines. Functional polymorphisms of the TH gene may be involved in the pathogenesis of neuropsychiatric diseases such as schizophrenia, affective disorders, and Parkinsonism. This study examined a possible association of two polymorphisms, both of which result in an amino acid change of the TH protein, with schizophrenia and Parkinson's disease (PD). The Val 81 Met polymorphism is a common variation, although its effect on the enzyme expression is unclear. Leu 205 Pro polymorphism is a rare mutation that is reported to cause Parkinsonism in infancy for individuals who are homozygous for the mutated type. We genotyped a Japanese sample of 194 schizophrenics, 99 patients with PD, and 161 controls for the Val 81 Met polymorphism by using mis-match PCR and digestion by the restriction enzyme BalI. There was no significant allelic or genotypic association of the Val 81 Met polymorphism with schizophrenia or PD. The Leu 205 Pro polymorphism was examined by using PCR and digestion by AluI; however, there was no individual who carried the mutated type of Pro 205 among 50 schizophrenics or 50 patients with PD. Thus we obtained no evidence for the involvement of the two structural mutations of the TH gene in the pathogenesis of schizophrenia or PD.