Objectives: The objective of this study is to examine the effect of fetal alcohol exposure on later substance dependence using an adoption study method. Methods: One hundred ninety-seven adoptees were interviewed for substance abuse disorders, including nicotine, alcohol, and drug dependence. Twenty-one adoptees had mothers who drank during pregnancy. Adoptees with fetal alcohol exposure were compared with those without fetal alcohol exposure for symptoms of adult nicotine, alcohol, and drug dependence. Results: Adoptee symptom counts for alcohol, drug, and nicotine dependence were higher for those exposed to alcohol in utero. The effect of fetal alcohol exposure remained after controlling for gender, biological parent alcohol dependence diagnosis, birth weight, gestational age and other environmental variables. Conclusions: Fetal alcohol exposure may produce increased risk for later nicotine, alcohol, and drug dependence. Possible effects of fetal alcohol exposure on development of adult substance use patterns needs attention in genetic studies of substance abuse.