OBJECTIVE: To report the therapeutic efficacy of venlafaxine and bupropion in a patient with treatment-refractory major depression. CASE SUMMARY: A 21-year-old white woman with chronic and recurrent major depression presented with lack of response to several antidepressants. On examination, the patient exhibited neurovegetative signs of depression, guilt feelings, and suicidal ideation. The patient was administered venlafaxine 75 mg three times daily. The dose was titrated to 150 mg three times daily over the next month. Later bupropion was instituted up to 100 mg three times daily over a four-month period. The patient responded favorably to combination therapy and has remained free of depression for approximately 23 months. DISCUSSION: Venlafaxine and bupropion are antidepressant agents with unique pharmacologic profiles, each effective in the treatment of depression. Recent data indicate that combinations of selective serotonin-reuptake inhibitors and bupropion can convert partial response to full response in patients with treatment-resistant depression. We considered whether a combination of venlafaxine and bupropion would reduce the depressive symptoms of a patient who was unresponsive to various classes of psychotropic agents. Gradual administration of venlafaxine and bupropion acted synergistically to significantly reduce depressive symptoms (p < 0.002) and significantly increase social function (p < 0.002) over a period of eight months. CONCLUSIONS: To our knowledge this is the first report of successful combination therapy with venlafaxine and bupropion in treatment of chronic recurrent and refractory major depression.