Substance use is common among youth; however, our understanding of co-morbid tobacco, alcohol and marijuana use remains limited. The school-environment may play an important role in the likelihood a student engages in high risk substance use behaviors, including co-morbid use. This study aims to: (i) describe the prevalence of co-morbid substance use behaviors among youth; (ii) identify and compare the characteristics of youth who currently use a single substance, any two substances, and all three substances; (iii) examine if the likelihood of co-morbid use varies by school and; (iv) examine what factors are associated with co-morbid use. This study used nationally representative data collected from students in grades 9 to 12 (n = 41,886) as part of the 2006-2007 Canadian Youth Smoking Survey (YSS). Demographic and behavioral data were collected including, current cigarette, alcohol and marijuana use. Results. 6.5% (n = 107,000) reported current use of all three substances and 20.3% (n = 333,000) of any two substances. Multi-level analysis revealed significant between school variability in the odds a student used all three substances and any two substances; accounting for 16.9% and 13.5% of the variability, respectively. Co-morbid use was associated with sex, grade, amount of available spending money and perceived academic performance. Co-morbid substance use is high among youth; however, not all schools share the same prevalence. Knowing the school characteristics that place particular schools at risk for student substance use is important for tailoring drug and alcohol education programs. Interventions that target the prevention of co-morbid substance use are required.