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Background The epidemiology of nosocomial bloodstream infections (NBSIs) in patients with coronavirus disease 2019 (COVID-19) is poorly understood, due in part to substantial disease heterogeneity resulting from multiple potential pathogens. Methods We identified risk factors for NBSIs and examined the association between NBSIs and mortality in a retrospective cohort of patients hospitalized with COVID-19 in 2 New York City hospitals during the height of the pandemic. We adjusted for the potential effects of factors likely to confound that association, including age, race, illness severity upon admission, and underlying health status. Results Between January 1 and October 1, 2020, 1403 patients had a positive blood culture, and 79 and 101 met the stringent criteria for NBSI among non-COVID-19 and COVID-19 patients, respectively. NBSIs occurred almost exclusively among patients who were severely ill with COVID-19 at hospital admission. NBSIs were associated with elevated mortality, even after adjusting for baseline differences in COVID-19 illness (55% cases vs 45% controls; P  = .13). Mortality was concentrated in patients with early-onset pneumonia caused by S. aureus and gram-negative bacteria. Less virulent Candida (49%) and Enterococcus (12%) species were the predominant cause of NBSI in the latter stages of hospitalization, after antibiotic treatment and COVID-19 treatments that attenuate immune response. Most Enterococcus and Candida infections did not have an identifiable source and were not associated with common risk factors for infection by these organisms. Conclusions Pathogen species and mortality exhibited temporal differences. Early recognition of risk factors among COVID-19 patients could potentially decrease NBSI-associated mortality through early COVID-19 and antimicrobial treatment. [ABSTRACT FROM AUTHOR]