To determine the impact of the Comprehensive Unit-Based Safety Program (CUSP) on patient safety, this study compared intensive care units participating in the program with units not participating. Although safety culture improved in units with CUSP implementation, the intervention did not reduce incidence of central line–associated bloodstream infections. These findings demonstrate that teamwork training approaches, while helpful, may not be sufficient to augment patient outcomes. Further study characterizing sites that improved versus those that did not may elucidate facilitators and barriers to achieving patient safety goals.