We investigated whether the plasma level of 3-methoxy-4-hydroxyphenylglycol (MHPG) could be used to predict the response to selective serotonin reuptake inhibitors (SSRIs) and serotonin noradrenaline reuptake inhibitors (SNRIs) in patients with major depressive disorder (MDD). Patients with MDD diagnosed by DSM-IV-TR were enrolled in the present study. Two hundred and forty participants were treated monotherapy with the SSRI paroxetine (n=81), selective serotonin and norepinephrine reuptake inhibitor antidepressant (SSNRI) duloxetine (n=49), the SNRI milnacipran (n=48), the SSRI fluvoxamine (n=63), or the SSRI escitalopram (n=27). The severity of depressive state was evaluated with the 17-item of Hamilton Rating Scale for Depression (HAMD17). The end-point point of the present study was week 8. Patients whose HAMD17 scores decreased ≥ 50% were defined as responders; others were non responders. Plasma MHPG levels were analyzed by high-performance liquid chromatography. A significant negative correlation was found between the change of plasma MHPG and the change of HAMD17 score in the responders to paroxetine or fluvoxamine. A trend for a positive correlation was found between the change of plasma MHPG and the HAMD17 score in the responders to milnacipran or duloxetine. These results suggest that MHPG might be a candidate for the prediction of treatment response in MDD patients.