Introduction: To create time for learner-centered forms of active learning in the classroom, didactic lectures are being replaced with instructor-guided independent learning (IGIL) assignments that students complete on their own outside of the formal educational setting. The effectiveness of IGIL assignments in supporting learning across the preclinical medical curriculum when applied to all learners in the same class of students has not been examined. Further, we have examined this performance across three class cohorts. Methods: In this retrospective cohort study, we compared student performance on questions from both IGIL assignments and didactic lectures that were items on the end-of-course summative examinations. Data were analyzed from three classes of graduating students in each of the 14 courses that comprise our preclinical medical curriculum. Results: The results of this study suggest that IGIL assignments were as effective as didactic lectures in supporting student learning in our preclinical medical curriculum. Importantly, IGIL assignments supported learning for both low and high performing students. Conclusions: Students can effectively learn from IGIL assignments when the assignments are well-designed and their importance in the curriculum is emphasized.