The authors studied the efficacy and safety of combined venlafaxine and quetiapine treatment for treatment-resistant depression (TRD) by dividing 95 TRD patients into two treatment groups: a combined venlafaxine (225 mg/day) and quetiapine (400 mg/day) group and a venlafaxine-only (225 mg/day) group for 8 weeks. Efficacy was assessed with the Hamilton Rating Scale for Depression, 17 items (Ham-D-17) and the Hamilton Rating Scale for Anxiety (Ham-A); safety was assessed with the Treatment-Emergent Symptom Scale (TESS). The two groups showed significant differences for the Ham-D-17 and Ham-A and no differences on the TESS. Combined venlafaxine and quetiapine treatment showed good efficacy and safety in TRD.