Many patients with major depressive disorder (MDD) present with concurrent substance use disorders (SUDs), which has been thought to impair their response to antidepressants. Clinicians often delay antidepressant treatment until sustained sobriety has been established. Unfortunately, these comorbid subjects are typically excluded from depression treatment trials, leaving a gap in understanding the treatment outcomes. In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, 2876 adult outpatients diagnosed with nonpsychotic MDD were prospectively treated with the selective serotonin-reuptake inhibitor (SSRI), citalopram, and returned for at least one post-baseline visit. Participants with SUD (29%) and without SUD (71%) were compared in regard to baseline clinical and sociodemographic features and treatment response. The group with MDD and SUD was further subdivided into those with alcohol only, drug only, and both alcohol and drug use. Despite clear sociodemographic and clinical differences, there were no significant differences between groups in the time to achieve response or rates of response to citalopram; however, those who endorsed both alcohol and drug use had significantly reduced rates of remission and significantly increased times to reach remission compared to the MDD group without SUD. In addition, subjects with MDD and SUD had higher risk of psychiatric serious adverse events (3.3% vs. 1.5%) and hospitalization (2.8% vs. 1.2%). The results indicate that first-line treatment with citalopram in depressed patients with alcohol or drug use respond as well as those without SUD. More intensive treatment is most likely needed for MDD patients with both drug and alcohol use disorders. © 2009.