The current study compared the prevalence of substance use and DSM-IV dependence in the USA and Australia. Participants aged 18-54 were selected from two cross-sectional nationally representative Australian (National Survey on Mental Health and Well-Being - NSMHWB, 1997, n = 7570) and American (National Epidemiologic Survey on Alcohol and Related Conditions - NESARC, 2001-2002, n = 29,673) household surveys. The NSMHWB utilised the Composite International Diagnostic Interview, whereas the NESARC used the Alcohol Use Disorder and Associated Disabilities Interview Schedule. The 12-month prevalence of alcohol use was lower in the USA (56.5%) than in Australia (77.2%), although the rates of alcohol dependence were similar in both countries. The USA had higher rates of alcohol dependence conditional on use (9.0%) compared to Australia (6.8%). Australians had higher levels of drug use, dependence, and conditional dependence than Americans (except for sedatives and opioids). The absence of significant interactions between country of interview and the common correlates of substance use disorders indicated that the influence of these factors was similar in the USA and Australia. In conclusion, the current investigation revealed striking differences in the rates of conditional drug dependence between Australia and the USA. The cross-national generalizability of the relationships between the common correlates and prevalence of substance use and dependence indicates that a similar process of vulnerability to dependence may be operating in the USA and Australia. In the future, these cross-national differences could be used to help better understand the factors that influence drug use and the development of dependence.