Alcohol dependence among Native Americans and Alaska Natives is twice that found in the general population. Alaska Natives are 7 times more likely to die of alcohol-related problems. This study investigated differences in the course and consequences of alcoholism and co-occurring polysubstance dependence in a sample of 582 alcohol-dependent Alaska Natives undergoing inpatient lifetime treatment in Anchorage between 1994 and 1999. Mean age was 33.9 years. Information on lifetime psychiatric symptoms and disorders was collected by using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA), a research diagnostic interview. Results indicate that in addition to alcohol dependence, the majority of subjects were dependent on other substances. Marijuana dependence was most common, followed by dependence on cocaine and opiates. Compared with subjects not dependent on any other drugs, subjects with co-occurring alcohol and opiate dependence showed significant differences in relation to age of first regular drink, intoxication, tolerance and withdrawal symptoms, number of medical problems, and number of psychological problems. More research and specific clinical interventions are needed for alcohol- and opiate-dependent Alaska Natives. Findings indicate the need for prevention and interventions in alcohol and illicit drug abuse in this population at an early age.