The aim of the present study was to test a possible effect of the G-protein beta3-subunit (Gbeta3) C825T gene variant on the antidepressant activity of selective serotonin reuptake inhibitors (SSRIs) in a sample of major and bipolar depressives, with or without psychotic features. Four hundred and ninety inpatients were treated with fluvoxamine 300 mg/day (n=362) or paroxetine 40 mg/day (n=128) and either placebo or pindolol in a double-blind design for 6 weeks. The severity of depressive symptoms was weekly assessed with the Hamilton Rating Scale for Depression. Gbeta3 allelic variants were determined in each subject using a PCR-based technique. Subjects with Gbeta3 T/T variants showed better response to treatment (P=0.009) and this effect was independent from analyzed demographic and clinical variables. These results confirm preliminary reports and shed further light on the genetics of the response to antidepressant treatments.