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Introduction: SARS-CoV-2 is a highly contagious virus, and despite professionals' best efforts, nosocomial COVID-19 (NC) infections have been reported. This work aimed to describe differences in symptoms and outcomes between patients with NC and community-acquired COVID-19 (CAC) and to identify risk factors for severe outcomes among NC patients. Methods: This is a nationwide, retrospective, multicenter, observational study that analyzed patients hospitalized with confirmed COVID-19 in 150 Spanish hospitals (SEMI-COVID-19 Registry) from March 1, 2020, to April 30, 2021. NC was defined as patients admitted for non-COVID-19 diseases with a positive SARS-CoV-2 test on the fifth day of hospitalization or later. The primary outcome was 30-day in-hospital mortality (IHM). The secondary outcome was other COVID-19-related complications. A multivariable logistic regression analysis was performed. Results: Of the 23,219 patients hospitalized with COVID-19, 1,104 (4.8%) were NC. Compared to CAC patients, NC patients were older (median 76 vs. 69 years; p < 0.001), had more comorbidities (median Charlson Comorbidity Index 5 vs. 3; p < 0.001), were less symptomatic (p < 0.001), and had normal chest X-rays more frequently (30.8% vs. 12.5%, p < 0.001). After adjusting for sex, age, dependence, COVID-19 wave, and comorbidities, NC was associated with lower risk of moderate/severe acute respiratory distress syndrome (ARDS) (adjusted odds ratio [aOR]: 0.72; 95% confidence interval [CI]: 0.59–0.87; p < 0.001) and higher risk of acute heart failure (aOR: 1.40; 1.12–1.72; p = 0.003), sepsis (aOR: 1.73; 1.33–2.54; p < 0.001), and readmission (aOR: 1.35; 1.03–1.83; p = 0.028). NC was associated with a higher case fatality rate (39.1% vs. 19.2%) in all age groups. IHM was significantly higher among NC patients (aOR: 2.07; 1.81–2.68; p < 0.001). Risk factors for increased IHM in NC patients were age, moderate/severe dependence, malignancy, dyspnea, moderate/severe ARDS, multiple organ dysfunction syndrome, and shock; odynophagia was associated with lower IHM. Conclusions: NC is associated with greater mortality and complications compared to CAC. Hospital strategies to prevent NC must be strengthened. [ABSTRACT FROM AUTHOR]