Based on their metabolic inactivation of dopamine and norepinephrine, genes encoding the catechol-O-methyltransferase (COMT) enzyme are appropriate candidates to consider in the pathogenesis of schizophrenia. COMT enzyme activity is regulated by a common polymorphism causing substantial variations in enzymatic activity, and evidence for allelic or genotypic association with cognitive and behavioral features of schizophrenia has been noted. Since the role of COMT in schizophrenia remains inconclusive, we determined whether any association exists between COMT genotypes and clinical symptomatology in a large cohort of schizophrenia subjects. DNA was extracted from peripheral blood in 111 patients with DSM-IV criteria schizophrenia (77 M, 34 F) and genotyped for COMT polymorphisms. Subjects were also were rated by means of the PANSS and the CGI. No association was found between COMT genotype or allele frequency and gender. No associations were observed between COMT and CGI or PANSS scores. Our findings do not support hypotheses regarding associations between COMT polymorphisms and clinical state in schizophrenia, contrary to other studies suggesting involvement of the COMT polymorphism with schizophrenia phenotype. Thus, while speculative, it may be suggested that a modifying gene may be required in order for the COMT polymorphism to manifest at the clinical level in schizophrenia with one set of susceptibility genes being more sensitive to COMT enzyme variability than others.