<i>Aims:</i> This study aimed to determine the relationship between the C825T polymorphism in the G-protein β3 subunit (GNB3) gene and the response to mirtazapine in a Korean population with major depressive disorder (MDD). <i>Method:</i> Mirtazapine was administered for 8 weeks to the 101 MDD patients who completed this study. All subjects were examined using the Structured Clinical Interview for DSM-IV, and the severity of depression was assessed using the 21-item Hamilton Depression Rating (HAMD-21) scale. <i>Results:</i> There was a significant main effect of time on the decrease in the HAMD-21 score during the 8-week study period. However, a main effect of or an interaction of genotype with time on the decrease in the HAMD-21 score during the 8-week study period was not found. ANOVA revealed no significant effects of the GNB3 C825T polymorphism on the decrease in the HAMD-21 score at each time period. <i>Conclusion:</i> Although the C825T polymorphism of the GNB3 gene may affect the pathogenesis of MDD, our results do not support the hypothesis that this polymorphism is involved in the therapeutic response to mirtazapine in Korean patients with MDD.