Objective: This report compares the baseline demographic and clinical characteristics of outpatients with nonpsychotic major depressive disorder (MDD) and a family history of substance use disorder (SUD) versus those with MDD and no family history of SUD. Method: Using data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, we grouped participants with MDD (DSM-IV criteria) according to presence or absence of family history of SUD based on participant report. Between-group comparisons were made of demographic and clinical characteristics, depressive symptoms, and psychiatric comorbidities. Patients were enrolled from July 2001 until August 2004. Results: Of 4010 participants, 46% had a positive family history of SUD. Those with a positive family history were less likely to be Hispanic (p = .0029) and more likely to be female (p = .0013). They were less educated (p = .0120), less likely to be married (p < .01), and more likely to be divorced (p < .01). They also reported an earlier age at onset of MDD, greater length of illness, and more major depressive episodes (all p < .001). They had an increased likelihood of recurrent MDD, more prior suicide attempts, and more concurrent psychiatric comorbidities, including posttraumatic stress disorder, SUD, and generalized anxiety disorder (all p < .0001). Conclusion: Depressed patients with a family history of SUD had a more severe previous course of depression, were more likely to have attempted suicide, and had a greater burden of psychiatric comorbid conditions than patients without such a family history. These findings represent important clinical features to be considered in the evaluation and treatment planning of patients with MDD.