We examined the effects of a professional development (PD) with coaching model designed to improve literacy and co-taught instruction for students with and without disabilities in co-taught content-area middle school classes. Eleven co-teaching pairs in nine schools were randomly assigned to the Content Area Literacy Instruction (CALI) condition (n = 7 pairs) or a business-as-usual comparison condition (n = 4 pairs). All 22 teachers individually completed researcher developed pre- and posttests of teacher knowledge and skills and perceived effectiveness of their personal ability and their co-teachers' ability. At pre- and posttest, students (n = 212) completed three measures of reading comprehension. CALI teachers demonstrated significantly higher scores than comparison teachers at posttest on a measure of knowledge and skills, perceived personal effectiveness, and perceived co-teachers' effectiveness. All CALI co-teaching pairs demonstrated high levels of fidelity. Students in the CALI classrooms demonstrated significant gains on an essential aspect of a researcher-developed measure of reading comprehension. However, the treatment effect was non-significant for the two standardized measures of reading comprehension. Results provide initial support for a model in improving teacher instructional outcomes and student academic outcomes.