The aims of this study were to examine whether use of tobacco, alcohol, and illicit drugs predicts dropout among secondary school students in Cape Town, South Africa. A self-report instrument was administered to 1,470 Grade 8 students. The proportion of students that dropped out of school between the onset of the study and 4 years later was 54.9%. After adjusting for a range of confounders, dropout was significantly predicted by absenteeism, poverty (as assessed by a possession index), and past month cigarette use, but not by past month alcohol use and lifetime illicit drug use. Contrary to findings from developed countries, alcohol and illicit drug use did not predict dropout. It is possible that predictors of dropout documented elsewhere may not be pertinent in developing countries. (Contains 2 tables.)