Accumulating evidence showed that brain-derived neurotrophic factor (BDNF) may be involved in the pathophysiology of schizophrenia. Decreased BDNF levels have been found in the serum of schizophrenic patients with mixed results. In the present study, we assessed serum BDNF levels in a large group of 364 schizophrenic patients (157 on clozapine, 89 on risperidone and 118 on typical antipsychotics), compared to 323 healthy control subjects matched for age and gender. The schizophrenia symptomatology was assessed by the Positive and Negative Syndrome Scale (PANSS), and serum BDNF levels were measured by sandwich ELISA. The results showed that BDNF levels were significantly lower in chronic patients with schizophrenia than in healthy control subjects (9.9+/-2.0 ng/ml vs.11.9+/-2.3 ng/ml, p<0.0001). Lower BDNF levels were observed in patients treated with risperidone (9.3+/-2.3 ng/ml) compared to those with clozapine (10.2+/-2.0 ng/ml, p<0.001) and typical antipsychotics (10.0+/-2.1 ng/ml, p<0.01). Furthermore, a stepwise multiple regression analysis identified types of antipsychotic drugs (beta=-0.37, t=-3.15, p=0.001) and BDNF levels (beta=-0.26, t=-2.51, p=0.014) as the influencing factor for the positive symptom subscore of PANSS. In addition, there was a sex difference in BDNF levels in patients with schizophrenia (9.7+/-1.9 ng/ml for males vs.10.4+/-2.1 ng/ml for female, p<0.005), but not in normal controls. Our findings indicated decreased BDNF serum levels in chronic patients with schizophrenia, which may be related to clinical phenotypes, including gender, antipsychotic treatment and the severity of psychotic symptoms.