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OBJECTIVE: Noninvasive positive-pressure ventilation (NPPV) emerged as an efficient tool for treatment of COVID-19 pneumonia. The factors influencing NPPV failure still are elusive. The aim of the study was to investigate the relationships between semiquantitative chest computed tomography (CT) scoring and NPPV failure and mortality in patients with COVID-19. DESIGN: Observational study. SETTING: Nonintensive care setting. PARTICIPANTS: A total of 112 patients consecutively admitted for COVID-19 pneumonia. INTERVENTIONS: Usual care including various degrees of respiratory support. MEASUREMENTS AND MAIN RESULTS: The semiquantitative CT score was calculated at hospital admission. Subgroups were identified according to the ventilation strategy used (oxygen delivered by Venturi mask n = 53; NPPV-responder n = 38; NPPV-failure n = 21). The study's primary endpoint was the use of NPPV. The secondary endpoints were NPPV failure and in-hospital death, respectively. CT score progressively increased among groups (six v nine v 14, p < 0.05 among all). CT score was an independent predictor of all study endpoints (primary endpoint: 1.25 [95% confidence interval {CI} 1.1-1.4], p = 0.001; NPPV failure: 1.41 [95% CI 1.18-1.69], p < 0.001; in-hospital mortality: 1.21 [95% CI 1.07-1.38], p = 0.003). According to receiver operator characteristics curve analysis, CT score was the most accurate variable for prediction of NPPV failure (area under the curve 0.862 with p < 0.001; p < 0.05 v other variables). CONCLUSIONS: The authors reported the common and effective use of NPPV in patients with COVID-19 pneumonia. In the authors' population, a semiquantitative chest CT analysis at hospital admission accurately identified those patients responding poorly to NPPV.