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The purpose of this study was to determine the impact of a flipped classroom method based on cognitive science of learning strategies on student performance and experience in a third-year pharmacotherapy course.The cognitive science of learning flipped classroom (CSL-FC) strategies in this study included pre-class learning (Preview), in-class application to cases (Retrieval), after-class learning (Spaced Retrieval), and post-module reflection (Deliberate Reflection) in a required pharmacotherapy course. During fall 2017, one instructor piloted the CSL-FC method. During fall 2018, this method expanded to four instructors. All other instructors used traditional lecture-based methods. The same multiple-choice exam questions were used both years. The average exam question scores between teaching methods were compared by independent t-test. Student focus groups were conducted after the 2017 semester. In 2018, students were surveyed using a 5-point Likert rating (1 = strongly agree, 5 = strongly disagree) to evaluate their experience.The 2017 and 2018 classes included 132 and 137 students, respectively. During the two years, exam question scores were significantly better with CSL-FC (n = 136 questions) compared to traditional (n = 110 questions) (88.8% vs 84.9%, respectively; P = .02). The focus group analysis revealed three main themes including a "love-hate relationship," "time," and "it works." Student agreement to the survey question "the cognitive science of learning flipped classroom helped me learn" was 2.18 (SD 1.12).Implementing a flipped classroom approach based on cognitive science of learning strategies positively impacted student performance and experience in a pharmacotherapy course.