Objective: To investigate the association between substance use disorders (SUDs) and the clinical presentation, risk factors, and correlates of major depressive disorder (MDD) by examining differences among 3 groups: (1) individuals with lifetime MDD and no comorbid SUD (MDD-NSUD); (2) individuals with comorbid MDD and SUD (MDD-SUD); and (3) individuals with substance-induced depressive disorder (SIDD). Method: Data were derived from the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (N = 43,093). Diagnoses were made using the Alcohol Use Disorder and Associated Disabilities Interview Schedule-DSM-IV Version. Results: The lifetime prevalence of MDD-NSUD was 7.41%, whereas those of MDD-SUD and SIDD were 5.82% and 0.26%, respectively. Overall, risk factors for MDD were more common among individuals with MDD-SUD and SIDD than among those with MDD-NSUD. Individuals with MDD-SUD and SIDD had similar rates of comorbidity with any psychiatric disorder, but both groups had higher rates than individuals with MDD-NSUD (odds ratio [OR] = 2.3; 95% CI, 1.9-2.7 and OR = 2.5; 95% CI, 1.4-4.4, respectively). Individuals with SIDD were significantly less likely to receive medication than those with MDD-SUD or MDD-NSUD (OR = 0.5; 95% CI, 0.3-0.9 for both groups). Conclusions: MDD-SUD is associated with high overall vulnerability to additional psychopathology, a higher number of and more severe depressive episodes, and higher rates of suicide attempts in comparison to individuals with MDD-NSUD. SIDD has low prevalence in the general population but is associated with increased clinical severity and low rates of medication treatment. Similar patterns of comorbidity and risk factors in individuals with SIDD and those with MDD-SUD suggest that the 2 conditions may share underlying etiologic factors. © Copyright 2012 Physicians Postgraduate Press, Inc.