Background and Objectives. The aim of this study is to compare clinical and epidemiological characteristics and outcomes in patients with versus without nosocomial COVID-19 after exposure to SARS-CoV-2 and to analyze the risk factors for severe outcomes of COVID-19 in a long-term hospital in Spain. Materials and methods. This retrospective, single-center observational study included all inpatients in a long-term hospital during a COVID-19 outbreak from 21 January to 15 March 2021. Results. Of 108 admitted patients, 65 (60.2%) were diagnosed with nosocomial COVID-19 disease (n = 34 women (52.3%), median age 77 years). In the univariable analysis, risk factors associated with nosocomial COVID-19 were dementia (OR 4.98 95% CI 1.58–15.75), dyspnea (OR 5.34 95% CI 1.69–16.82), asthenia (OR 5.10, 95% CI 1.40–18.60) and NECesidades PALiativas (NECPAL) (OR 1.28 95% CI 1.10–1.48). In the multivariable analysis, risk factors independently associated with nosocomial COVID-19 infection were dyspnea (aOR 7.39; 95% CI 1.27–43.11) and NECPAL (aOR 1.25; 95% CI 1.03–1.52). Of the 65 patients diagnosed with nosocomial COVID-19, 29 (44.6%) died, compared to 7/43 (16.2%) non-infected patients (OR 4.14, 95% CI 1.61–10.67). Factors associated with mortality in nosocomial COVID-19 were confusion (aOR 3.83; 95% CI 1.03–14.27) and dyspnea (aOR 7.47; 95% CI 1.87–29.82). The NECPAL tool played an important predictive role in both nosocomial COVID-19 infection and mortality (aOR 1.19, 95% CI: 1.00–1.41). Conclusions. In a long-term hospital, nosocomial COVID-19 main clinical characteristics associated with infection were dyspnea and NECPAL. Mortality was higher in the group with nosocomial COVID-19; risk factors were confusion and dyspnea. The NECPAL tool may help to predict progression and death in COVID-19.