Background: Alcohol and other substance use disorders (SUD) pose major problems of morbidity and mortality in some American Indian communities, but little is known about the clinical characteristics, risk factors, and consequences of combined alcohol and other substance use disorders (multi-substance use disorder, MSUD) in those communities. Methods: Using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA), in a community sample of 876 American Indians, the clinical characteristics of lifetime DSM-5 moderate or severe alcohol use disorder alone (AUD alone) (n = 146) and MSUD (defined as alcohol and >= 1 other SUD) (n = 284) were evaluated and compared to 347 participants with no lifetime SUD (no SUD). Results: The majority (57%) of participants with a SUD had multi-substance use disorder and 94% of those were with AUD. Stimulants (cocaine and/or amphetamine) and/or cannabis were the most common other SUDs. Participants with AUD alone were more likely to be male and have an earlier age of first alcohol intoxication than those with no SUD. Those with MSUD were more likely to have dropped out of high school, have antisocial personality disorder (ASPD) or conduct disorder (CD), have earlier ages of first alcohol intoxication and first use of cannabis and stimulants, an earlier age of onset of AUD, and more of several AUD symptoms than those with AUD alone, but the same temporal course and time to remission of AUD. Conclusions: MSUD is prevalent in this sample, is associated with multiple comorbidities and denotes a more severe alcohol syndrome than AUD alone. (c) 2016 Elsevier Ireland Ltd. All rights reserved.