Schizophrenia is a complex neuropsychiatric disorder strongly associated with dopamine dysregulation. Catechol-O-methyl-transferase (COMT) is a candidate gene for schizophrenia that encodes an enzyme involved in the metabolic inactivation of dopamine. The COMT Val158Met polymorphism has been associated with schizophrenia and has significant inter- and intra-ethnic variations. We examined a possible association between the COMT Val158Met polymorphism and schizophrenia in Saudis, taking into account gender and functional symptoms. Saudi subjects including 172 unrelated schizophrenia patients and 177 matched controls were analyzed for allele and genotype distribution of the COMT Val158Met polymorphism. We found significant differences in allele and genotype frequencies between patients and controls. The frequencies of Met158 allele (A) and genotype Val158Met (GA) were significantly higher in patients compared to those in controls. On the other hand, the frequencies of Val158 allele (G) and genotype Val158Val (GG) were significantly higher in controls than those in patients. We found a significant association of the COMT Val158Met polymorphism with schizophrenia. Moreover, male patients with the COMT Val158Met polymorphism had increased risk for schizophrenia compared to female subjects. However, no association was noticed with the COMT Val158Met polymorphism and negative or positive symptoms of schizophrenia. These results provide evidence for a role of the COMT Val158Met polymorphism in the etiopathophysiology of schizophrenia in Saudi population. It appears that the association of the COMT Val158Met polymorphism with schizophrenia is mediated by gender.