The most effective ways to promote learning and inspire careers related to science, technology, engineering, and mathematics (STEM) remain elusive. To address this gap, we reviewed the literature and designed and implemented a high-fidelity, medical simulation-based Harvard Medical School MEDscience course, which was integrated into high school science classes through collaboration between medical school and K–12 faculty. The design was based largely on the literature on concepts and mechanisms of self-efficacy. A structured telephone survey was conducted with 30 program alumni from the inaugural school who were no longer in high school. Near-term effects, enduring effects, contextual considerations, and diffusion and dissemination were queried. Students reported high incoming attitudes toward STEM education and careers, and these attitudes showed before versus after gains (P < .05). Students in this modest sample overwhelmingly attributed elevated and enduring levels of impact on their interest and confidence in pursuing a science or healthcare-related career to the program. Additionally, 63% subsequently took additional science or health courses, 73% participated in a job or educational experience that was science related during high school, and 97% went on to college. Four of every five program graduates cited a health-related college major, and 83% offered their strongest recommendation of the program to others. Further study and evaluation of simulation-based experiences that capitalize on informal, naturalistic learning and promote self-efficacy are warranted.