BACKGROUND: Although substance use is commonly associated with mental disorders, limited data on this association are available from low and middle income countries such as South Africa. The aims of the study were i) to determine patterns of substance use in young adults, ii) to identify trends of common psychiatric disorders in relation to use of specific substances, and iii) to determine whether specific psychiatric disorders were associated with use of specific substances in the South African population. METHODS: Data were drawn from the South African Stress and Health (SASH) study, a nationally-representative, cross-sectional survey of South African households that forms part of a World Health Organisation (WHO) World Mental Health (WMH) initiative to standardise information on the global burden of mental illness and its correlates. Data from a subset (n=1766; aged 18 to 30 years) of the SASH sample of 4351 individuals were analysed. The Composite International Diagnostic Interview Version 3 (CIDI 3.0) was used to elicit basic demographic details and information regarding mental illness and substance use. Multiple regression analyses, adjusted for age and gender, were used to identify associations between mental disorders and substance use. RESULTS: Significant associations were found between substance use and mood and anxiety disorders, with a particularly strong relationship between cannabis use and mental disorder. CONCLUSION: The results are consistent with those from previous studies, and reinforce the argument that comorbid substance use and mental disorders constitute a major public health burden.