BACKGROUND: The purpose of this study was to examine substance use and dependence among cocaine dependent subjects and their siblings compared to individuals recruited from the same neighborhood and their siblings in order to better understand family and neighborhood contributions to the development of dependence. METHODS: Cocaine dependent subjects were recruited through treatment centers. Community-based subjects were matched to cocaine dependent index cases on age, ethnicity, gender, and zip code. One full sibling for each case and community-based subject participated. RESULTS: Cocaine dependent subjects were significantly more likely than community-based subjects to use all substances studied and were 2-10 times more likely to be dependent on alcohol and other illicit drugs. Dependence only on cocaine was uncommon (<10%). The siblings of cocaine dependent subjects had higher rates of substance use and were 1.3-3 times more likely to have a diagnosis of substance dependence compared siblings of community-based subjects. However, when analyses focused only on those who ever used a specific substance, the siblings of cocaine dependent cases were at a similar or modestly elevated risk (1.5 times) of developing dependence. CONCLUSIONS: Cocaine dependence is characterized by polysubstance use and dependence. In addition, the prevalence of substance dependence in the community subjects was higher than reported for the general population, indicating that cocaine dependent cases live in high-risk communities with elevated prevalence of substance dependence. A potential intervention to decrease the family clustering of dependence is to reduce the initiation of drug use in relatives at risk.