BACKGROUND: The clinical effects of antidepressant combinations vs. monotherapy as initial treatment for major depression with melancholic features (MDD-MF) are unknown. METHODS: Outpatients with chronic or recurrent major depression (MDD) were randomized to initial treatment with escitalopram+placebo (the MONO condition), bupropion-sustained release+escitalopram, or venlafaxine-extended release+mirtazapine (the COMB conditions) in the Combining Medications to Enhance Depression Outcomes (CO-MED) trial. Secondary data analyses were conducted to compare demographic and clinical characteristics, and contrast clinical responses according to drug treatment, in patients with MDD-MF (n=124) and non-melancholic MDD (n=481). RESULTS: While numerically lower, remission rates in MDD-MF did not differ significantly from those with non-melancholic MDD either at 12 (33.1% vs. 41.0%, aOR 1.16, p=0.58) or 28 (39.5% vs. 46.8%, aOR=1.02, p=0.93) weeks of treatment. Remission rates did not differ significantly between combination and monotherapy groups in either MDD-MF or non-melancholic MDD patients at either time point. Similar conclusions were reached for response rates, premature study discontinuation, and self-rated depression symptom severity. LIMITATIONS: This is a secondary analysis of data from the CO-MED trial, which was not designed to address differential treatment response in melancholic and non-melancholic MDD. CONCLUSIONS: We found no evidence of differential remission or response rates to antidepressant combination or monotherapy between melancholic/non-melancholic MDD patients, or according to antidepressant treatment group, after 12 and 28 weeks. Melancholic features may not be a valid predictor of more favorable response to antidepressant combination therapy as initial treatment.