This article summarizes data from a 2004 study of over 300,000 high school students (aged 13–18 years) in nine South American countries. A probabilistic sample targeted urban secondary schools, utilizing a self-administered questionnaire on prevalence and frequency of substance use. Multivariate analysis showed that volatile substances were the first or second most commonly reported substances used after alcohol and cigarettes in all countries (lifetime prevalence range: 2.67% [Paraguay] to 16.55% [Brazil]). Previous studies have highlighted volatile substance misuse among street children, whereas this study demonstrates that it is common among South American high school students.This work was supported through a collaborative effort between the United Nations Office on Drugs and Crime and the Organization of American States through the Inter-American Drug Abuse Control Commission (CICAD). Study design and project implementation was done through CICAD at the Inter-American Observatory on Drugs. In addition, fieldwork was done through the National Drug Commissions of Argentina, Bolivia, Brazil, Chile, Ecuador, Paraguay, Peru, and Uruguay. Support was also received by NIH/NIDA research project award R01DA021181 as well as from the School of Social Work Vivian A. and James L. Curtis School of Social Work Research and Training Center at the University of Michigan. In addition, support was received from the 1C Research Productivity Grant from National Council of Scientific Development (CNPQ) of the Ministry of Science and Technology of Brazil. (United Nations Office on Drugs and Crime; Organization of American States through the Inter-American Drug Abuse Control Commission (CICAD); R01DA021181 - NIH/NIDA; School of Social Work Vivian A. and James L. Curtis School of Social Work Research and Training Center at the University of Michigan; National Council of Scientific Development (CNPQ) of the Ministry of Science and Technology of Brazil