Background: It has been suggested that the antidepressant effect of laser acupuncture involves modulation of the default mode network (DMN) or resting state network (RSN). In this study, the authors investigated changes in the DMN during laser acupuncture in depressed and nondepressed participants. Objective: To aim of this study was to determine if the modulation of the DMN effects by laser acupuncture in depressed participants are different from those of nondepressed participants. Design: Randomized stimulation was performed with laser acupuncture on four putative antidepressant acupoints (LR 14, LR 8, CV 14, and HT 7) in a block on-off design, while the blood oxygenation level-dependent (BOLD) fMRI response was recorded from each subject's whole brain on a 3T scanner. DMN patterns of the participants were identified, using an independent component analysis. The identified DMN components from both the nondepressed group and the depressed group were then analytically compared using SPM5. Setting: This study took place at a research institute. Subjects: Ten nondepressed participants and 10 depressed participants (DS) as confirmed by the Hamilton Depression Rating Scale (HAM-D) participated in this study. Intervention: Low Intensity Laser Acupuncture. Main outcome measures: Significant DMN patterns in one group were greater than those in the other group. Results: The nondepressed participants had significant modulation of DMN in the frontal region at the medial frontal gyrus (verum laser>rest, p<0.001) for three acupoints (LR 14, LR 8, and CV 14). For the depressive participants, the DMN modulation occurred at the inferior parietal cortex and the cerebellum (verum laser>rest, p<0.001). Conclusions: Laser acupuncture on LR 8, LR 14, and CV 14 stimulated both the anterior and posterior DMN in both the nondepressed and depressed participants. However, in the nondepressed participants, there was consistently outstanding modulation of the anterior DMN at the medial frontal gyrus across all three acupoints. In the depressed participants, there was wider posterior DMN modulation at the parieto-temporal-limbic cortices. This is part of the antidepressant effect of laser acupuncture.