BACKGROUND: Most patients with major depressive disorder (MDD) report clinically significant sleep problems. Pre-treatment insomnia has been associated with poorer treatment outcomes in some antidepressant trials, leading to suggestions that combined treatment regimens may be more successful in this subgroup. This study investigated this question using data from the CO-MED trial. METHODS: Adult outpatients with chronic and/or recurrent MDD were randomly assigned in 1:1:1 ratio to 28 weeks of single-blind, placebo-controlled antidepressant treatment with (1) escitalopram+placebo, (2) bupropion-sustained-release+escitalopram, or (3) venlafaxine-extended-release+mirtazapine. We compared baseline characteristics, tolerability, and treatment outcomes at 12 and 28 weeks for patients with and without pre-treatment insomnia. RESULTS: Of the 665 evaluable patients, the majority (88.3%) reported significant pre-treatment insomnia. Those with pre-treatment insomnia were more likely to be female (69.3% vs. 57.7%) and African-American (29.1% vs. 11.8%). Those with pre-treatment insomnia symptoms reported higher rates of concurrent anxiety disorders, lower rates of alcohol and substance use disorders, and greater impairment in psychosocial functioning. The two groups did not differ in either tolerability or treatment outcomes among the three antidepressant treatments. CONCLUSIONS: Insomnia symptoms, while common in patients with chronic/recurrent MDD were not predictive of response, remission, or tolerability with either single or combined antidepressant medications.