Matrix metalloproteinase-9 (MMP-9) plays a role in many pathological conditions (e.g. cancer and heart disease). Recently, MMP-9 has been implicated in the activity of the prefrontal cortex and we therefore hypothesized that the MMP-9 gene may be associated with schizophrenia. We genotyped the functional -1562C/T polymorphism in a group of 442 schizophrenia patients and in 558 healthy control subjects. A significant preponderance of C/C genotype and C allele was found in the schizophrenia subjects compared to healthy controls. The results may provide the first evidence for involvement of the MMP-9 gene in the pathogenesis of schizophrenia and could also contribute to explaining a genetic connection between schizophrenia and some somatic illnesses.