Central-line–associated bloodstream infections (CLABSIs) are a significant cause of preventable harm. A collaborative project involving a multifaceted intervention was used in the Michigan Keystone Project and associated with significant reductions in these infections. This intervention included the Comprehensive Unit-based Safety Program, a multifaceted approach to CLABSI prevention, and the monitoring and reporting of infections. The purpose of this study was to determine whether the multifaceted intervention from the Michigan Keystone program could be implemented in Connecticut and to evaluate the impact on CLABSI rates in intensive care units (ICUs). The primary outcome was the NHSN-defined rate of CLABSI. Seventeen ICUs, representing 14 hospitals and 104,695 catheter days were analyzed. The study period included up to four quarters (12 months) of baseline data and seven quarters (21 months) of postintervention data. The overall mean (median) CLABSI rate decreased from 1.8 (1.8) infections per 1,000 catheter days at baseline to 1.1 (0) at seven quarters postimplementation of the intervention. This study demonstrated that the multifaceted intervention used in the Keystone program could be successfully implemented in another state and was associated with a reduction in CLABSI rates in Connecticut. Moreover, even though the statewide baseline CLABSI rate in Connecticut was low, rates were reduced even further and well below national benchmarks.