Objective · To explore the correlation of serum S100B protein with depressive episode of bipolar disorder (BD) and its prognosis.  Methods · Based on BD criteria of Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM- Ⅳ ), 80 patients with depressive episode of BD (case group) and 42 healthy controls (control group) were enrolled. Patients were randomly assigned into quetiapine group who were treated with lithium and quetiapine and modified electroconvulsive therapy (MECT) group who received lithium and MECT. The serum S100B level and Hamilton Rating Scale for Depression (HAMD) were assayed before and after 4-week treatment.  Results · The serum S100B levels before treatment in patients with depressive episode of BD were significantly higher than those in healthy controls (P=0.000). The levels of S100B in both drug and MECT groups decreased after 4-week treatment. The HAMD score after treatment significantly decreased than that before treatment (P=0.000). Pearson correlation analysis showed that the change of S100B level was positively correlated with the change of HAMD score before and after treatment in case group (r=0.33, P=0.013).  Conclusion · S100B may be associated with depressive episode of BD and its prognosis.