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Introduction: Alpha asymmetry of the left and right frontal hemisphere is a potential biomarker for major depressive disorder (MDD). Neurofeedback (NFB) is a clinical intervention program for regulating brain activity and decreasing alpha asymmetry. The purpose of this study was to explore the efficacy of NFB among patients with MDD. Methods: Fourteen patients with MDD were randomly assigned to a NFB group that received neurofeedback training 1 hr weekly for 6 weeks and to a control group that was treated without training. A 5-min resting baseline of electroencephalogram (EEG) was recorded at F3 (left) and F4 (right) before and after NFB, and the alpha power was analyzed as an asymmetry index (A1). Results: The A1 of the control group decreased from pre- to post-interventions while the A1 of the NFB group increased from pre- to post-interventions. Anxiety and depression scores of the responder group decreased from pre- to post-interventions, while the scores of the non-responder group increased from pre-to post-interventions. Conclusion: Patients who respond to the NFBtraining showed a decrease in anxiety and depression scores compared to those who do not. This study indicated that NFB could improve left frontal hypoarousal or right frontal hyperarousal among patients with MDD.