Health systems have widely employed teamwork training as a strategy for improving patient safety. With increasingly constrained hospital budgets, there has been a new focus on showing the business case for patient safety programs. This study calculated the return on investment of a system-wide crew resource management training program at a large academic medical center. Over 3 years, the program trained approximately 3000 health system employees, costing an estimated $3.6 million, due to programmatic costs, time away from work, and leadership time. However, there was a 25% reduction in observed to expected adverse events across the same time period, which, if attributed to this training program, would result in an estimated $12–$28 million in savings, yielding at least a $9 million return on investment. A prior AHRQ WebM&M perspective discussed strengthening the business case for patient safety.