Native Americans have some of the highest rates of alcohol abuse and dependence, yet potential biological risk factors associated with the problem drinking seen in some tribes remain relatively unknown. The amplitude of the P3 component of the event-related potential (ERP) is perhaps the most studied electrophysiological "marker" of potential vulnerability to alcohol dependence, yet it has not been investigated in Native Americans. Forty-seven, non-alcohol-dependent Native American Mission Indian men between the ages of 18 and 25 years participated in the study. ERPs were collected at 60 minutes following both alcohol (0.56 g/kg) and placebo intake. No relationship was found between P3 amplitude and degree of Native-American heritage (NAH), or family history (FH) of alcohol dependence. The results of this study did, however, replicate previous findings that the P3 component of the ERP is sensitive to the effects of alcohol. A reduction in the P3a component across the scalp was found in these Native American men following alcohol when compared with placebo ingestion. P3 response to alcohol, although not influenced by a subject's NAH or FH, was influenced by the presence of a polymorphism in the alcohol metabolizing enzyme alcohol dehydrogenase (ADH). Men with an ADH2 x 3 allele had significantly higher amplitude P3 components at placebo and also demonstrated more alcohol-induced reductions in P3 amplitude than men with ADH2 x 1 alleles only. In addition, individuals with low P3 amplitude in the placebo condition had less of a reduction or an actual increase in P3a and P3b amplitudes following alcohol intake. Given that a less intense response to alcohol has been associated with greater risk for the development of alcohol-related problems, these data suggest the presence of certain biological variables within this Native American population that may confer both risk and protection for the future development of alcohol dependence.