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OBJECTIVE To examine the impact of SARS-CoV-2 infection on CLABSI rate and characterize the patients who developed a CLABSI. We also examined the impact of a CLABSI-reduction quality-improvement project in patients with and without COVID-19. DESIGN Retrospective cohort analysis. SETTING Academic 889-bed tertiary-care teaching hospital in urban Los Angeles. PATIENTS OR PARTICIPANTS Inpatients 18 years and older with CLABSI as defined by the National Healthcare Safety Network (NHSN). INTERVENTION(S) CLABSI rate and patient characteristics were analyzed for 2 cohorts during the pandemic era (March 2020-August 2021): COVID-19 CLABSI patients and non-COVID-19 CLABSI patients, based on diagnosis of COVID-19 during admission. Secondary analyses were non-COVID-19 CLABSI rate versus a historical control period (2019), ICU CLABSI rate in COVID-19 versus non-COVID-19 patients, and CLABSI rates before and after a quality- improvement initiative. RESULTS The rate of COVID-19 CLABSI was significantly higher than non-COVID-19 CLABSI. We did not detect a difference between the non-COVID-19 CLABSI rate and the historical control. COVID-19 CLABSIs occurred predominantly in the ICU, and the ICU COVID-19 CLABSI rate was significantly higher than the ICU non-COVID-19 CLABSI rate. A hospital-wide quality-improvement initiative reduced the rate of non-COVID-19 CLABSI but not COVID-19 CLABSI. CONCLUSIONS Patients hospitalized for COVID-19 have a significantly higher CLABSI rate, particularly in the ICU setting. Reasons for this increase are likely multifactorial, including both patient-specific and process-related issues. Focused quality-improvement efforts were effective in reducing CLABSI rates in non-COVID-19 patients but were less effective in COVID-19 patients.