Sub-threshold hypomanic symptoms are common in major depressive disorder. This study evaluated the prevalence, the clinical and sociodemographic correlates, and the overall and differential effects of the presence/absence of sub-threshold hypomanic symptoms at baseline on acute-phase treatment outcomes with bupropion-plus-escitalopram combination, escitalopram monotherapy, and venlafaxine-plus-mirtazapine combination. Combining medications to enhance depression outcomes (CO-MED) trial participants (n = 665) were designated as sub-threshold hypomanic symptoms present (Altman Self-Rating Mania Scale score (ASRM) ≥ 1) or absent (ASRM = 0) and compared on clinical and sociodemographic features and remission rates. Participants with sub-threshold hypomanic symptoms (n = 335/665, 50.4%) were more likely to be black and non-Hispanic, have comorbid medical and psychiatric disorders, experience longer index episodes, and report lower depression severity and psychosocial impairment. Intent-to-treat remission rates were lower overall (absent = 42.7%, present = 34.0%, p = 0.02), with escitalopram monotherapy (absent = 45.8%, present = 31.6%, p = 0.03), and with venlafaxine-XR-plus-mirtazapine combination (absent = 44.4%, present = 30.1%, p = 0.03) but not with bupropion-plus-escitalopram combination (absent = 37.7%, present = 40.0%, p = 0.73). Participants without sub-threshold hypomanic symptoms were more likely to remit than those with such symptoms overall [odds ratio (OR) = 1.49], with escitalopram monotherapy (OR = 1.71), and with venlafaxine-plus-mirtazapine combination (OR = 1.97) but not with bupropion-plus-escitalopram combination (OR = 0.96), even after controlling for baseline depression severity, psychosocial impairment, and number of comorbid psychiatric disorders. Sub-threshold hypomanic symptoms (found in about 50% of patients in this report) were associated with lower remission rates with escitalopram monotherapy and with venlafaxine-plus-mirtazapine combination but not with the bupropion-plus-escitalopram combination.