One approach some U.S. schools now use to combat high rates of adolescent substance use is school-based mandatory-random student drug testing (MRSDT). Under MRSDT, students and their parents sign consent forms agreeing to the students' participation in random drug testing as a condition of participating in athletics and other school-sponsored competitive extracurricular activities. This study is the largest experimental evaluation to date of school-based MRSDT. The study tested the effectiveness of MRSDT in reducing substance use among high school students. The results of this study found that students subject to MRSDT reported less substance use than comparable students in schools without MRSDT. However, the program had no spillover effects on the substance use reported by students not subject to testing and had no effect on any group of students' intentions to use substances. The program had no unintentional effects on the proportion of students participating in activities subject to drug testing or on students' attitudes toward school and perceived consequences of substance use.