ABSTRACT. Objective: Among Asian American young adults, variations in alcohol-metabolizing genes (i.e., aldehyde dehydrogenase [ALDH2] and alcohol dehydrogenase [ADH1B]) are protective, whereas Korean ethnicity, family history of alcohol problems (FH), and acculturation represent risk factors for alcohol misuse. This study aims to integrate these genetic and environmental factors in a sample of Asian Americans expressing a wide range of alcohol use behaviors and problems. Method: Participants were 97 Asian American young adults (42% female) recruited as heavy and light drinkers (n = 49 and 48, respectively). Participants completed the Alcohol Use Disorders Identification Test, Timeline Followback, Vancouver Acculturation Index, and Family Tree Questionnaire. All participants provided buccal cell samples for DNA analysis. Results: Family history-positive (FH+) subjects reported greater alcohol use than family history-negative (FH−) subjects. A FH × ALDH2 interaction was observed such that FH− subjects demonstrated no ALDH2 effect, yet in FH+ subjects, the ALDH2*2 genotype was associated with increased alcohol use. A significant main effect of acculturation was also moderated by FH such that the positive association between acculturation and alcohol use was greater among FH+ subjects and, in particular, among FH+ men. Conclusions: Although preliminary, these results suggest that the potential protective effects conferred by ALDH2 and ADH1B are moderated by FH, such that a positive FH appeared to abolish the protective effect of these genes. Further, acculturation was associated with greater alcohol use in FH+ subjects only. If replicated in larger samples, these data suggest that alcohol-metabolism genes may not be protective in the context of high environmental risk. (J. Stud. Alcohol Drugs, 76, 690-699, 2015)