Children with cancer are a subset of patients with central lines with distinct risk factors for infection including periods of prolonged neutropenia and compromised mucous membrane integrity. This article relates the implementation of principles of practice-based evidence to identify interventions in addition to best practice maintenance care bundles to reduce central line–associated bloodstream infections involving viridans group streptococci and coagulase-negative staphylococci on an inpatient pediatric oncology unit. Review of individual events combined with review of current clinical practice guided the development of structured protocols emphasizing routine oral care and general supportive cares. Key principles of the protocols emphasized a 1-2-3 mnemonic and included daily bathing, twice daily oral care, and out-of-bed activity 3 times daily. Poisson regression identified a significant main effect for time period for central line–associated bloodstream infection rates involving both viridans group streptococci and coagulase-negative staphylococci. Significant differences were present between the preintervention baseline and implementation of the supportive care protocols. Project outcomes demonstrate the added value of using principles of practice-based evidence to guide the development of interventions to improve clinical care when evidence-based sources are limited.