Background: The 2010 Cochrane Collaboration Review reported laser acupuncture as being effective in depression. The treatment was on LR 8, LR 14, CV 14, and HT 7 over 12 sessions within a 2-month period. Objective: The aim of this study was to investigate the biological plausibility of low-intensity laser acupuncture as an antidepressant treatment. Design: Randomized stimulation with a fiber-optic infrared laser on these acupoints and KI 3 acupoint. We used a blocked design, alternating laser and placebo laser/rest blocks, while the blood oxygenation level-dependent (BOLD) fMRI response was recorded from the whole brain on a 3T MRI scanner. Setting: This study took place at the research institute. Subjects: Ten subjects were studied, as confirmed by the Hamilton Depression Rating Scale (HAM-D 17). Intervention: Low-intensity laser acupuncture. Main outcome measures: Significant brain patterns for each acupoint greater than the other acupoints and placebo. Results: Each acupoint laser stimulation condition resulted in a different activation size and pattern of neural activity. Regions with significantly increased activation and deactivation compared to placebo included fronto-limbic-striatal brain regions. There was no significant activation or deactivation with KI 3. Blinding was afforded with the block design and the infrared laser. Conclusions: There is positive biological evidence to support the empirical evidence for laser acupuncture in the treatment of depression. With its minimal adverse effect profile and ease of application, laser acupuncture should be included in depression management strategies.