OBJECTIVE: To examine the 3-year course of multiple co-occurring substance use disorders (SUDs) based on longitudinal survey data from a large, nationally representative sample. METHODS: National estimates of the prevalence of DSM-IV SUDs were derived by analyzing data from structured, face-to-face diagnostic interviews as part of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), which collected data from a large, nationally representative sample of noninstitutionalized US adults at 2 waves (2001-2002 and 2004-2005; N = 34,653). RESULTS: US adults with multiple past-year SUDs at Wave 1 were substantially more likely than those with an individual past-year SUD or no SUD at Wave 1 to report at least 1 past-year SUD at Wave 2 (66.3% vs 46.0% vs 6.9%, respectively). There were several sociodemographic characteristics and psychiatric disorders (ie, male, younger age, never married, sexual minority identity, nicotine dependence, mood disorder, and personality disorder) associated with increased odds of developing multiple SUDs and having 3-year persistence of multiple SUDs. The majority of adults with multiple past-year SUDs had a lifetime personality disorder and did not utilize substance abuse treatment or other help-seeking. CONCLUSIONS: Multiple SUDs are associated with a more persistent 3-year course of disease over time relative to individual SUDs. Despite a more severe 3-year course and higher rates of comorbidity with other psychiatric disorders, the majority of US adults with multiple SUDs do not utilize substance abuse treatment or other help-seeking. Clinical assessments and the substance abuse literature tend to focus on drug-specific individual SUDs rather than considering the more complex multiple SUDs, which can be more challenging to treat.