Our objective was to assess the effectiveness and safety of the combination of duloxetine and bupropion for treatment-resistant major depressive disorder (TRD). A retrospective chart review was conducted to identify patients with major depressive disorder (MDD) who had not experienced full remission of symptoms following an adequate trial of either duloxetine (n 5 3) or bupropion (n 5 7), and who then received the combination of these two antidepressants for TRD. Ten patients [37.2711.3 years of age, five women, baseline Clinical Global Impressions (CGI) scale score 4.471.1], seven of whom had not remitted following treatment with bupropion (330767 mg, 20.5712.2 weeks), and three of whom had not remitted following treatment with duloxetine (90730 mg, 1872 weeks) received at least 4 weeks of combination treatment. The CGI was administered when the combination was first prescribed, and following 8.874.0 (range, 4-16) weeks of treatment. There was a significant decrease in CGI-S (Severity) scores (4.471.1 to 2.170.9, P o .0001) following combination treatment. Three (30%) patients were remitters at follow-up, and six (60%) were responders who did not achieve full symptom remission. The mean maximum adjunctive duloxetine and bupropion doses were 60.0717.3 mg and 175.07114.5 mg, respectively. Side effects reported during combination treatment were nausea (n 5 2), dry mouth (n 5 2), jitteriness/agitation (n 5 2), fatigue/drowsiness (n 5 2), increased blood pressure (n 5 1), increased sweating (n 5 1), insomnia (n 5 1), pruritus (n 5 1), headache (n 5 1), sexual dysfunction (n 5 1), and weight gain (n 5 1). Although preliminary, these results suggest a possible role for the combination of duloxetine and bupropion for TRD. Depression and Anxiety 23:178-181, 2006.