Aims: To compare the prevalence of alcohol and drug use, dependence and treatment seeking in the United States of America and Australia. Design: Two cross-sectional national surveys assessing substance use and DSM-IV substance dependence in the USA and Australia. Setting and participants: Age-matched cohorts (18-54 years old) were selected from nationally representative Australian (National Survey of Mental Health and Well-being, 1997, n = 7570) and American (National Comorbidity Survey, 1992, n = 7423) household surveys. Measurements: Both studies utilised a structured interview based on the Composite International Diagnostic Interview (CIDI). Findings: The 12-months prevalence of alcohol use was substantially higher in Australia (77.2%) than in the U.S. (46.3%) and the rates of alcohol dependence were also higher in Australia, although rates of alcohol dependence conditional on use were similar (6.8 and 6.5%, respectively). In contrast, although rates of use of drugs were similar in the two countries, rates of drug dependence and the probability of dependence conditional on use were higher in Australia than in the U.S. Importantly, the absence of significant interactions between correlates of alcohol and drug use disorders and country indicated that the influence of these factors was consistent across the two countries. Conclusions: Despite relatively similar cultural influences in Australia and the U.S. interesting cross-national differences emerged in the use of alcohol and drug dependence among those who used drugs and treatment seeking among people diagnosed with dependence. The cross-national generalizability of the associations between common correlates and rates of alcohol and drug use and dependence indicates that similar process of vulnerability to dependence may be operating in the two countries. Future research could usefully exploit these cross-national differences to help elucidate the cultural and structural factors influencing drug use, the development of dependence and treatment seeking.