BACKGROUND Sedentary behavior and physical activity are not mutually exclusive behaviors. The relative risk of overweight for adolescents who are highly sedentary and highly physically active is unclear. A better understanding of the relationship between sedentary behaviors, physical activity, and body mass index (BMI) would provide insight for developing interventions to prevent or reduce overweight. METHODS Using the physical activity module of the School Health Action, Planning and Evaluation System (SHAPES), we collected data from 25,060 students in grades 9 through 12 from 76 secondary schools in Ontario, Canada. Sex-specific logistic regression analyses were performed to examine how BMI, weight perceptions, social influences, team sports participation, and smoking behavior were associated with being 1) high active-high sedentary, 2) low active-low sedentary, and 3) low active-high sedentary. RESULTS Low active-high sedentary boys were more likely to be overweight than high active-low sedentary boys (adjusted odds ratio [AOR], 1.60; 95% confidence interval [CI], 1.01-2.58). When compared with high active-low sedentary girls, girls who were low active-high sedentary (OR, 2.24; 95% CI, 1.23-4.09) or high active-high sedentary (OR, 1.91; 95% CI, 1.01-3.61) were more likely to be overweight. CONCLUSIONS Sedentary behavior may moderate the relationship between physical activity and overweight. Developing a better understanding of sedentary behavior in relation to physical activity and overweight is critical for preventing and reducing overweight among youth.