Background: Evidence shows poor adherence to strategies for reducing morbidity and mortality in intensive care unit (ICU) patients receiving mechanical ventilation globally. Best practice management relies on training all members of the interprofessional ICU team, each with complementary roles in patient management., Objectives: To develop and evaluate a novel two-phase, train-the-trainer, interprofessional and multicultural "Best Practice Management of the Ventilated ICU Patient" multimodality, simulation-enhanced curriculum for Thai education leaders in critical care., Methods: In phase 1 (Oregon Health and Science University cohort), two groups of nine ICU nurses and one critical care physician representing experts in critical care and education from a large hospital system in Thailand participated in a weeklong, immersive course consisting of didactic, simulation, and in situ immersive sessions focused on best practice management of mechanically ventilated ICU patients, as well as training in our educational techniques. Outcomes were assessed with pre- and postcourse knowledge assessments and overall course evaluation. In phase 2 (Thai cohort), participants from phase 1 returned to Thailand and implemented a lower fidelity curriculum in two hospitals, using the same pre- and posttest knowledge assessment in 41 participants, before the onset of the coronavirus disease (COVID-19) 6 pandemic., Results: In the Oregon Health and Science University cohort, the mean pretest knowledge score was 58.4 ± 13.2%, with a mean improvement to 82.5 ± 11.6% after completion of the course ( P , 0.05). The greatest improvements were seen in respiratory physiology and advanced/disease-specific concepts, which demonstrated absolute improvements of 30.4% and 30.6%, respectively ( P < 0.05). Participants had a high degree of satisfaction, with 90% rating the course as "excellent" and .90% reporting that the course "greatly improved" their understanding of best practices and comfort in managing mechanical ventilation. The Thai cohort had a mean baseline score of 45.4 ± 15.0% and a mean improvement to 70.3 ± 19.1% after training ( P < 0.05). This cohort also saw the greatest improvement in respiratory physiology and advanced/disease-specific concepts, with 26.2% and 26.3% absolute improvements, respectively ( P < 0.05)., Conclusion: A novel, two-phase, interprofessional, multicultural, simulation-enhanced train-the-trainer curriculum was feasible and effective in improving education in best practice management of mechanically ventilated patients and may be a useful model for improving the care of ICU patients across the world., (Copyright © 2022 by the American Thoracic Society.)