Tobacco and alcohol use by adolescents are major public health concerns in South Africa. However, the extent to which key psychosocial risk factors for tobacco use and alcohol use by adolescents in South Africa are shared or unshared is unclear. This study sought to examine the shared and unshared risk factors for tobacco and alcohol use among adolescents in Johannesburg. Method: Participants comprised 736 males and females aged 12-17 years who were recruited via a household survey conducted during 2004. The participants were interviewed from a questionnaire comprising measures of personal, family (parental bonding and family legal drug use), and contextual (school and neighbourhood) factors. Separate multiple logistic regression analyses were conducted to predict lifetime alcohol use and lifetime tobacco use from variables within each domain (personal, family, and contextual), controlling for demographic factors. Results: Personal, family (parental bonding), and contextual factors (school factors) were primarily shared risk factors for tobacco and alcohol use, while family legal drug use and neighbourhood factors were largely unshared. Conclusions: Interventions addressing personal, parenting and schooling factors are likely to impact on preventing both tobacco and alcohol use, whereas interventions focused on ameliorating family drug use and neighbourhood factors may need to be more substance-specific.