A multimodal hospital-wide central line–associated bloodstream infection (CLABSI) risk reduction strategy was implemented over a 20-month period at an Australian center. Reduced CLABSI rates were observed in both intensive care units (ICUs) (incidence rate ratio [IRR], 0.39; P < .001) and non-ICU wards (IRR, 0.54; P < .001). The median time to CLABSI onset was 7.5 days for ICU events and 13 days for non-ICU events. The timing of infection demonstrates the need for more careful attention to postinsertion care and access of central venous catheters.