The high prevalence of alcohol abuse and alcohol dependence among Native Americans may be mediated by unique environmental and genetic factors in this population. One factor that may influence the development of alcoholism is variability in alcohol metabolism. To determine factors that contribute to differences in alcohol elimination rates within a Native American population, this study evaluated healthy southern California Mission Indian men between the ages of 18 and 25 years. Each man drank a dose of alcohol, 0.56 g/kg of body weight as a 20% by volume solution, at approximately 9:00 AM after eating a low-fat breakfast and having fasted overnight. The drink was consumed within 7 min, and the concentrations of alcohol in blood were determined before and at 15, 30, 60, 90, 120, and 150 min after beverage ingestion. Rates of alcohol elimination were calculated from the pseudolinear slope of the blood alcohol versus time curve. The influences of estimated body water, recent drinking history, recent smoking history, polymorphism at the ADH2 and ADH3 loci, family history of alcoholism, and percentage Native American heritage on alcohol elimination rate were determined using multiple regression analyses. Estimated body water accounted for a significant proportion of the variance in alcohol elimination rate. There was also a nonsignificant trend for subjects with an ADH2*3 allele (n = 6) to have faster rates of alcohol elimination than those with ADH2*1 alleles only (n = 33). Given the high prevalence of alcoholism and alcohol-related health problems among Native Americans, the results from this study suggest that evaluation of alcohol metabolism and genotypes of the alcohol-metabolizing enzymes in Native American populations merits further study.