Little is known of the relationship between the least restrictive environment (LRE) provision of the Individuals With Disabilities Education Act (IDEA) and postsecondary participation for secondary students with disabilities despite the current policy emphasis on college and career readiness for all students. In this study, we examined the instructional setting in English/language arts and mathematics among secondary students with disabilities using data from the National Longitudinal Transition Study–2. Logistic regression analyses revealed that students with disabilities were 2 times more likely to participate in 2- and 4-year programs if they received general education instruction in math. Follow-up moderator analyses showed the likelihood of 4-year postsecondary participation among students with hearing, speech, visual, orthopedic, and other health impairments was significantly amplified if they received language arts instruction in general education classrooms. These findings serve as useful baseline data to compare with student outcomes during and after the No Child Left Behind Act and will ultimately inform transition planning for secondary students with disabilities.