Central line-associated bloodstream infection (CLABSI) is associated with significant morbidity and mortality. A quality improvement project was conducted to decrease CLABSI rates by 50% across all ICUs in a tertiary care hospital (Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates). A multifaceted interventional program was implemented in a drive to reduce CLABSI rates. Stage 1 of the intervention entailed implementation of a central line insertion bundle, an insertion checklist, dedicated central line trolleys, education of all staff involved in insertion and maintenance of central lines, and empowerment of nurses. Stage 2 entailed implementation of a maintenance bundle and a CLABSI prevention policy and inclusion of central line assessment in the daily goals. Stage 3 was implemented in the form of CLABSI champions, spot checks on maintenance techniques, and review of every CLABSI. Stage 4 entailed the implementation of a Comprehensive Unit-based Safety Program (CUSP). Stage 5 consisted of a "back to basics" campaign, which included refocusing on basic evidence-based care bundles, introduction of bundle-compliance verification, and educational sessions and awareness programs. Overall CLABSI rates significantly decreased (p < .0001) from a mean of 2.99 (standard deviation [SD], 1.69) in the preimplementation period (January 2008-June 2011) to 1.47 (SD, 1.01) in the postimplementation period (July 2011-August 2014) across all ICUs. Overall, there were significantly more months with CLABSI-free days in the post-implementation than in the preimplementation period. The combination of evidence-based interventions, standardization of procedures, teamwork, and front-line staff involvement in the decision-making process contributed to decreases in CLABSI rates across three ICUs.