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Background: Substance abuse among American Indians/Alaska Natives (AI/ANs) is a significant and long-standing health problem in the U.S. Two-thirds of American AIs/ANs reside in the urban setting. However, studies analyzing substance use characteristics among urban AI/ANs are very limited.  Methods:Substance use patterns among a sample of AI/ANs (n = 77) and other ethnic/racial groups in Los Angeles County at high risk of substance abuse were analyzed utilizing three datasets from programs targeting individuals at high risk for substance abuse and risky sexual behaviors.  Results:Compared to all other ethnic/racial groups, AI/ANs demonstrated significantly younger age of onset of alcohol, marijuana, methamphetamine, and “other” drug use, higher correlations of age of first use of amphetamine with a measure of the drug's reinforcement, and higher mean number of illicit drug injections in the 30 days before being interviewed.  Conclusions:Results from this study highlight a critical need for furthering our understanding of substance abuse problems among urban AI/ANs.(Am J Addict 2012;00:1–8)