This study examined the efficacy of a curriculum-based intervention for high school science students. Specifically, the intervention was two years of research-based, multidisciplinary curriculum materials for science supported by comprehensive professional development for teachers that focused on those materials. A modest positive effect was detected when comparing outcomes from this intervention to those of business-as-usual materials and professional development. However, this effect was typical for interventions at this grade span that are tested using a state achievement test. Tests of mediation suggest a large treatment effect on teachers and in turn a strong effect of teacher practice on student achievement—reinforcing the hypothesized key role of teacher practice. Tests of moderation indicate no significant treatment by demographic interactions.