Brain-derived neurotrophic factor (BDNF) has been proposed as a risk factor for schizophrenia, but no consistent association between BDNF Val66Met polymorphism and schizophrenia has been established. Therefore, analyses with larger sample sizes and better methodology are needed. To examine whether BDNF Val66Met polymorphism is associated with schizophrenia, schizophrenia patients (n=251) and healthy volunteers (n=284) were recruited for a case-control analysis. Pretreatment psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS) in a subset of 125 hospitalized schizophrenia patients who were drug-free or drug-naive. Genotyping was performed using polymerase chain reaction, restriction fragment length polymorphism (RFLP), and direct screening techniques. With the exception of nominally significant associations between BDNF Val66Met variation and PANSS total, negative, or general scores, no association between the BDNF Val66Met polymorphism and schizophrenia was found. However, this polymorphism may reduce psychopathology, in particular negative symptoms, in schizophrenia.