Patients with febrile neutropenia (FN) often are subject to antibiotic and diagnostic test overuse. We sought to improve appropriate use of antimicrobials and diagnostic tests for patients with FN. We used a blended quality approach with Lean Six Sigma tools and iterative improvement of a clinical decision aid to guide providers through empirical antimicrobial selection and diagnostic evaluation of patients with FN during a yearlong period. We evaluated the incidence of nonadherence to best practice before, during, and after rollout of a clinical decision aid in conjunction with an educational initiative. At baseline, 71% of patients with FN had at least one critical deviation from best practice. During the project, the percentage decreased to 27.3%; 4 months after the project was completed, the percentage was 33.3% (P = .04). A clinical decision aid can improve adherence to best practices for the empirical management of FN.