Objective To investigate the immunologic mechanism of acupuncture at Bǎihuì(百 会 GV 20) and Zúsānlǐ(足三里 ST 36) for treatment of depression. Methods Eighty-four cases of depression patients were randomly divided into an electroacupuncture observation group(group A), an electroacupuncture control group(group B) and a medication control group(group C), 28 cases in each group. Bǎihuì(百会 GV 20) and Zúsānlǐ(足三里 ST 36) were used in the group A; Tàichōng (太冲 LR 3), Sānyīnjiāo (三阴交 SP 6), Nèiguān (内关 PC 6) and Shénmén (神门 HT 7) were used in the group B; and the group C was treated with oral administration of Fluoxetine. The scores of Hamilton Depression Scale (HAMD) were tested and the level of serum interleukin 1(IL-1β), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α) were measured by Enzyme Linked Immunosorbent Assay (ELISA)before and after treatment. Results Their scores of HAMD were obviously decreased after treatment in three groups(all P0.01). In the group A, 2 cases were cured, 19 cases were markedly effective, 5 cases were effective and 2 cases were failed. In the group B, 16 cases were markedly effective, 12 cases were effective. While in the group C, 1 case was cured, 17 cases were markedly effective, 7 cases were effective and 3 cases were failed. The grade distribution of clinical effect showed that the effect of group A was better (P0.05). The levels of serum IL-1β and IL-6 in the three groups were obviously decreased after treatment (P0.05, P0.01), while there was no significant difference between the level of serum TNF-α before and after treatment. Conclusion The effect of electroacupuncture observation group is superior to those of electroacupuncture control group and medication control group.All of these three methods can clear the inflammatory cytokines such as IL-1β and IL-6 away and improve the symptoms of depression.