The localization of 5-hydroxytryptamine6 (5-HT6) receptor in the limbic and cortical regions, and the high affinity of atypical antipsychotic drugs such as clozapine for the receptor, suggest the possible involvement of the receptor in the pathogenesis of schizophrenia. In this study, we searched systematically for polymorphisms in the 5'-upstream region of the human 5-HT6 receptor gene. We identified a trinucleotide repeat polymorphism, (GCC)2/3, at a nucleotide position between -1093 and -1085 bp upstream from the translation start site. Subsequent case-control association study did not demonstrate significant differences of genotype and allele frequency between 206 controls and 246 patients with schizophrenia. Our results suggest that the 5-HT6 receptor gene polymorphism does not confer increased susceptibility to schizophrenia.