Background: Bipolar disorder is a very common, often misdiagnosed mental disorder strongly associated with comorbidity, disability, and premature mortality. Bipolar depression (i.e., depressive episode in bipolar disorder) is poorly responsive to available treatments. Acupuncture at five Zang-shu and Ge-shu, a prescription from Dr. Leting Wang, is a popular therapy for depression in China. Its effectiveness and safety for bipolar depression is yet to be verified by clinical study. Methods/design: The study is a single-center, prospective, randomized controlled trial involving 72 patients diagnosed with bipolar depression. Participants will be randomized either to the study group or the control group in a 1:1 ratio. All participants will receive mood stabilizer therapy. In addition, the study group will receive acupuncture therapy at five Zang-shu and Ge-shu, three times per week. The control group will orally take the antidepressant bupropion. Observation and intervention will last for 8 consecutive weeks. Outcome measurements include Hamilton Depression Rating Scale-17 (HAMD-17), Hamilton Anxiety Rating Scale (HAMA), Clinical Global Impression Scale (CGI), Young Manic Rating Scale (YMRS), Treatment Emergent Symptom Scale (TESS), serum levels of anti-inflammatory cytokines (IL-4, IL-10, TGF-β), pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), brain-derived neurotrophic factor (BDNF) and C-Reactive Protein (CRP). Assessments will be conducted at baseline, 1st, 2nd, 4th and 8th week after randomization. Safety assessments will be performed throughout the study. Discussion: The results of this study are expected to verify the effectiveness and safety of acupuncture at five Zang-shu and Ge-shu for bipolar depression, and explore its therapeutic mechanisms from the point of anti- inflammation.