Background: Prior research has shown that adoptees have a higher rate of substance use disorders (SUDs) than nonadoptees. But these findings have not been verified with a population-based sample of adult adoptees in the United States. Also, no previous adoption study has measured the prevalence of each specific substance use disorder (SUD). We aimed to compare lifetime prevalence rates and odds ratios of SUDs in adopted and nonadopted adults. Methods and Findings: The data come from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). The main outcome measure was the prevalence of lifetime SUDs in adopted (n = 378) and nonadopted adults (n = 42503). Adoptees and nonadoptees were compared to estimate the odds of lifetime SUDs using logistic regression analysis. Adoptees had higher prevalence rates of lifetime SUDs than nonadoptees. Overall, adoptees had a 1.87-fold increase (adjusted odds ratio [AOR] 1.87, 95% CI 1.51-2.31) in the odds of any lifetime SUD compared to nonadoptees. For each SUD, adoptees had higher odds for alcohol abuse/dependence (AOR 1.84), nicotine dependence (AOR 1.78), cannabis abuse/dependence (AOR 1.77), cocaine abuse/dependence (AOR 2.54), amphetamine abuse/dependence (AOR 3.14), hallucinogen abuse/dependence (AOR 2.85), opioid abuse/dependence (AOR 2.21), and other drug abuse/dependence (AOR 2.87) compared to nonadoptees. This study also identified two adoption-specific risk factors (Hispanic, never married) associated with any lifetime SUD. Conclusions: This study demonstrated an increased risk of lifetime SUDs in adopted adults. The findings can be useful for clinicians and policy makers to provide education, prevention, and support for adoptees and their families.