Alcohol and illicit drug abuse and dependence continue to be of great national concern in the United States, as is true in other nations. The National Survey on Drug Use and Health (NSDUH) provides national annual estimates of substance use and abuse/dependence among the U.S. civilian, noninstitutionalized population aged 12 years or older. We conducted a clinical validation study of the substance use disorder questions of the NSDUH instrument using a sample of 288 adults and adolescents recruited from the community and outpatient substance abuse treatment programs in North Carolina. Using the Structured Clinical Interview for DSM-IV (SCID-IV) for adults and the Pittsburgh Adolescent Alcohol Research Center's Structured Clinical Interview (PAARC-SCID) for adolescents, we computed the psychometric properties of the NSDUH questions. We found the level of agreement between the NSDUH and the SCID/PAARC-SCID interviews to be fair to moderate overall. There was somewhat better agreement for dependence than for abuse and for adults than for adolescents.