OBJECTIVES: To investigate prevalence and the factors influencing substance use among rural high school pupils in KwaZulu-Natal in order to develop and implement intervention programmes. DESIGN: Cross-sectional study. SETTING: Twenty-eight high schools in southern KwaZulu-Natal. SUBJECTS: One thousand three hundred and eighteen grade 10 pupils. OUTCOME MEASURES: An anonymous self-reporting questionnaire was used to investigate the use of alcohol, tobacco (cigarettes), cannabis and solvents. RESULTS: Of the male scholars, 52.9% (95% confidence interval (CI): 45.4-60.3) reported ever using alcohol, 16.9% (CI: 11.5-24.0) reported using cannabis, and 13.1% (CI: 7.2-22.5) had smoked more than one cigarette daily. Among male pupils 45.5% (CI: 38.6-52.6) had inhaled benzine and 34.6% (CI: 28.0-41.8), thinners; 7.4% (CI: 3.4-15.2) had used cocaine and 4.1% (CI: 1.0-10.6), crack. Female pupils reported significantly less use of alcohol (25.5%, CI: 17.6-35.3), cannabis (2.3%, CI: 1.3-4.1), cigarettes (more than one daily) (2.0%, CI: 1.0-4.1), and inhalation of benzine (18.8%, CI: 13.8-25.2) and thinners (10.8%, CI: 7.2-16). Logistical regression indicated that the odds of smoking cigarettes increased significantly (p < 0.0005) with use of the other substances. CONCLUSION: The results of this study confirm the prevalence of multi-substance use among pupils at the majority of rural high schools in this district and the need for targeted interventions to reduce/prevent this.