Central Line-Associated Bloodstream Infections (CLABSIs) decreased in U.S. hospitals over the last decade, but CLABSI rates increased during the COVID-19 pandemic disrupting the downward trend. This study explored factors contributing to the reduction of CLABSI, identifying deviations in infection prevention and control protocol during the pandemic, actions taken to address the increase in CLABSI, and factors promoting sustained progress. This qualitative study used the National Healthcare Safety Network data. The Centers for Disease Control and Prevention identified hospitals with elevated CLABSI standardized infection ratios (SIR) >1 between Q1 2019 - Q4 2021 followed by four quarters of sustained reduction (CLABSI SIR <1). Joint Commission researchers conducted semi-structured phone interviews with infection preventionist professionals from six hospitals representing these performance patterns. Interview themes suggested that staffing shortages (83%) and less vigilant central line practices (100%) contributed to increased CLABSI SIR during the pandemic. Organizations described evidence-based interventions, such as using chlorhexidine gluconate for skin preparation, along with other innovative strategies they used to establish reduced CLABSI rates. Despite challenges faced during the COVID-19 pandemic, some health care organizations have excelled in their efforts to reduce and sustain low rates of CLABSI by implementing evidence-based practices, innovative solutions, and education.