The genes involved in signal transduction are major candidates in association studies on affective disorders and responses to antidepressants. We investigated whether the C825T polymorphism of the b3 subunit of G protein (GNB3) gene is associated with the symptom severity or treatment response of major depressive disorders (MDDs) in a Korean sample of 106 MDD patients; our study also included 133 healthy controls. Hypertensive subjects were excluded from the study because association between GNB3 variants and hypertension has been reported in previous studies. We found significantly more carriers of the 825T allele in MDD patients than in normal controls (w 2 ¼ 6.37, P ¼ 0.012; OR ¼ 2.19, 95% CI 1.18-4.05). The T-allele carriers showed higher scores than those with the CC genotype in the baseline total and in some subcategories of the Hamilton Depression Rating Scale (Po0.05). We also found a statistically significant association between T-allele carriers and antidepressant treatment response (Po0.05). These results suggest that the T allele of the C825T polymorphism in the GNB3 gene is associated with MDD. It was also demonstrated that MDD patients bearing the T allele had a severe symptomatology and a better response to antidepressant treatment than patients without the T allele.