S100B is a calcium-binding protein, mainly produced and secreted by astrocytes, and it mediates the interaction among glial cells and between glial cells and neurons. Recently, several studies have shown increased serum 100B levels in patients with schizophrenia, suggesting that S100B might be relevant to the pathophysiology of schizophrenia. To examine the potentially differential effect of clozapine compared to typical antipsychotics on serum S100B and the relationship between S100B levels and psychopathology in patients with schizophrenia, 63 physically healthy patients with schizophrenia were compared with 50 age-, sex-matched normal controls. The psychopathology of patients was assessed by the Positive and Negative Syndrome Scale (PANSS). Serum S100B levels were measured by sandwich ELISA. The results showed that S100B levels were significantly elevated in chronic patients with schizophrenia than in healthy controls (p<0.0001). As compared with healthy controls, there was a significant increase in S100B levels in patients treated with both clozapine and typical antipsychotics (both p<0.0001). However, no significant difference in S100B was found between patients treated with clozapine and typical antipsychotic subgroups (p>0.05). Furthermore, there was no significant correlation between S100B and standardized drug doses or the duration of taking neuroleptic medications (both p>0.05). In addition, no significant correlation was observed between S100B and PANSS total score and its subscale scores (all >0.05). These findings suggest that serum S100B levels in chronic schizophrenia under antipsychotic medication may be increased, suggesting that a dysfunction of astrocytes and/or oligodendrocytes may play a role in the pathogenesis of schizophrenia. Long term treatment with both typical and atypical antipsychotics may produce similar effects on the S100B serum levels, which however remains to be characterized in a large sample of first-episode, medication-naïve patients with schizophrenia using a longitudinal design.