We investigated the relationship between family structure and substance use in a sample of 2,138 public middle school students in a southern state. The CDC Middle School Youth Risk Behavior Survey was utilized and adjusted logistic regression models were created separately for four race/gender categories (African American females/males, and Caucasian females/males) to examine associations among selected drug use variables (tobacco, alcohol, marijuana and inhalants). Analyses were adjusted for social economic status. Results suggested differences (p less than or equal to 0.05) among race/gender groups for the protective effect of living in an intact family (both mother and father, real or adoptive) regarding substance use among middle school students. In addition, family structure appeared to have a stronger relationship with substance use for Caucasians as opposed to African American adolescents. Caucasian adolescents living in cohabitated family households were more likely to report substance use, when compared to those living in intact two-parent households. Adolescents who are undergoing parental divorce may need special attention as they transition into new family structures.