Objective: Our aim is to determine the lifetime and past-year prevalence estimates of multiple Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM-5) substance use disorders (SUDs) among U.S. adults. Methods: The 2012â€”2013 National Epidemiologic Survey on Alcohol and Related Conditions featured in-person interviews with a nationally representative sample of adults aged 18 and older. Results: The majority of past-year nonalcohol DSM-5 SUDs had at least 1 other co-occurring past-year SUD, ranging from 56.8% (SEÂ =Â 3.4) for past-year prescription opioid use disorder to 97.5% (SEÂ =Â 2.7) for past-year hallucinogen use disorder. In contrast, only 15.0% (SEÂ =Â 0.6) of past-year alcohol use disorders had a co-occurring past-year SUD. The odds of past-year multiple SUDs were greater among males, younger adults, African-Americans, and those with mood, personality, posttraumatic stress, or multiple psychiatric disorders. Conclusions: Assessment, diagnosis, and treatment often focus on individual substance-specific SUDs rather than multiple SUDs, despite evidence for substantial rates of polysubstance use in clinical and epidemiological studies. There are notable differences in the prevalence of multiple SUDs between alcohol use disorders and other nonalcohol SUDs that have important clinical implications; for example, multiple SUDs are more persistent than individual SUDs. These findings suggest that clinical assessment and diagnosis should screen for multiple SUDs, especially among adults with nonalcohol DSM-5 SUDs.