Background: Chaihu-Shugan-San (CHSGS) is a well-known Chinese traditional prescription used for depression. Objective: To observe the regional cerebral blood flow (rCBF) changes in patients with major depression and to investigate rCBF and clinical response to CHSGS. Materials and Methods: A total of 33 unmedicated patients with major depression and 12 healthy comparison subjects underwent single photon emission computed tomography (SPECT) imaging. A total of 33 unmedicated patients with major depression all met the diagnostic criteria of stagnation of liver qi of traditional Chinese medicine and were divided into two groups: CHSGS group (n = 20) and fluoxetine group (n = 13). SPECT imaging was restudied in posttreatment. Results: SPECT detected abnormalities in all (100.0%) patients both in CHSGS group and fluoxetine group. All healthy subjects were normal results. The depressed patients showed rCBF decreased in the multiple regions. The semiquantitative values of bilateral frontal and left temporal lobes both in CHSGS group and fluoxetine group were lower than that in healthy group (P < 0.05). Reexamined SPECT after 8 weeks treatment with CHSGS showed the consistency between the increase in perfusion defects and the improvement of clinical cerebral symptoms. The semiquantitative values increased in posttreatment, when compared with pretreatment (P < 0.05). Conclusion: SPECT represents a sensitive tool to detect the major depressive disorder, which show the rCBF decreased. rCBF perfusion defects can be reversed and clinical symptoms can be improved by CHSGS treatment. CHSGS treatment is effective, well-tolerated, and safe for depression. By semiquantitative analysis, SPECT can objectively detect rCBF changes that is useful for guiding treatment.