BACKGROUND: Sepsis is a common cause of hospitalization among Medicare beneficiaries, often leading to prolonged hospital stays and high costs. PURPOSE: To estimate the impact of registered nurse (RN) staffing and skill mix on hospital lengths of stay and associated costs for Medicare beneficiaries with sepsis. METHODS: A retrospective, cross-sectional analysis was conducted using 2018 data from 2,107 acute care hospitals, including 653,496 patients with sepsis. FINDINGS: A one-unit increase in RN hours per patient day and a 1% increase in RN skill mix reduced hospital stays by 2% and 1%, respectively. Enhancing staffing to nine RN hours per patient day and an 80% RN skill mix could save 63,580 inpatient days annually, reducing costs by 52.9 million. Further increases to 11 RN hours and an 85% skill mix could save 31.9 million. DISCUSSION: Better RN staffing and skill mix can improve patient outcomes and yield significant cost savings.