Patients with major depressive disorder (MDD) often present with concurrent substance use disorders (SUD) involving alcohol and/or illicit drugs. This analysis compares the depressive symptomatic presentation and a range of clinical and demographic features of patients with MDD and concurrent SUD symptoms vs those without SUD symptoms, to clarify how these two differ and to determine whether concurrent SUD symptoms may alter the clinical presentation of MDD. The first 1500 outpatients with nonpsychotic MDD enrolled in the Sequenced Treatment Alternatives to Relieve Depression study were divided into those with and without concurrent SUD symptoms as ascertained by a self-report instrument, the Psychiatric Diagnostic Screening Questionnaire (PDSQ). Of the 1484 cases with completed baseline PDSQ, 28% (n = 419) of patients with MDD were found to endorse symptoms consistent with current SUD. Patients with symptoms consistent with SUD were more likely to be men (P < .0001), to be either divorced or never married (P = .018), to have a younger age of onset of depression (P = .014), and to have a higher rate of previous suicide attempts (P = .014) than those without SUD symptoms. Patients with major depressive disorder who have symptoms consistent with SUD endorsed greater functional impairment attributable to their illness than those without concurrent SUD symptoms (P = .0111). The presence of SUD symptoms did not alter the overall depressive symptom pattern of presentation, except that the dual-diagnosed patients had higher levels of hypersomnia (P = .006), anxious mood (P = .047), and suicidal ideation (P = .036) compared to those without SUD symptoms. In conclusion, gender, marital status, age of onset of major depression, functional impairment, and suicide risk factors differ in depressed patients with concurrent SUD symptoms compared to those without SUD comorbidity.