Although dysfunction of catechol-O-methyltransferase (COMT)-mediated dopamine transmission is implicated in the etiology of schizophrenia, the human COMT gene has not been associated consistently with schizophrenia. The purpose of this study was to investigate whether the COMT gene is associated with the development of schizophrenia and whether the polymorphisms of this gene influence the psychopathological symptoms in patients with schizophrenia. Fourteen polymorphisms of the COMT gene were analyzed in a case-control study of 876 Han Chinese individuals (434 patients and 442 controls). All participants were screened using a Chinese version of the modified Schedule for Affective Disorders and Schizophrenia-Lifetime Version (SADS-L) and all patients met the criteria for schizophrenia. Furthermore, pretreatment of psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS) in a subset of 224 hospitalized schizophrenia patients, who were drug-naÏve or drug-free, to examine the association between clinical symptomatology and COMT polymorphisms. No significant differences in allele or genotype frequencies were observed between schizophrenia patients and controls, for all variants investigated. Haplotype analysis showed that three haplotype blocks of the COMT gene were not associated with the development of schizophrenia. Moreover, these COMT polymorphisms did not influence the PANSS scores of schizophrenia patients. This study suggests that the COMT gene may not contribute to the risk of schizophrenia and to the psychopathological symptoms of schizophrenia among Han Chinese.