S100B protein is a calcium-binding protein mostly derived from glial cells, which exerts trophic or toxic effects on neural cell depending on its concentration. It has been reported that S100B played an important role as a potential marker in psychiatric disorders. Thus, we will explore the clinical implication of S100B in major depression, especially the effect of gender and numbers of depressive episodes on S100B. The levels of serum S100B were measured with enzyme-linked immunosorbent assay (ELISA) in 54 patients with major depression and 35 age-matched healthy controls. The S100B levels in major depressed patients were significantly higher than those in controls. The serum S100B levels in female patients were significantly higher than those in male patients. Patients with recurrent depressive episodes had significantly higher S100B levels than those in first-episode depression. Serum S100B levels were significantly positive related with the numbers of depressive episode, family history and cognitive disturbance scores. These findings confirmed an increase in serum S100B levels in major depressive patients and presence of a sexual dimorphism. Moreover, numbers of depressive episodes in depression seemed to have an additional increasing effect on S100B levels.