Background: Severe patients hospitalized with COVID-19 suffered secondary infections which greatly increased the length of hospital stay and the mortality. We aimed to explore risk factors of secondary infections that can help clinicians early implement preventive measures to dispose of severe and critical inpatients with COVID-19.Methods: A case-control study enrolled 238 severe and critical patients with COVID-19. Characteristics of cases and controls were compared.Results: Severity of illness on admission, ICU admission, ventilator, central venous catheterization were common in the cases, however almost none of these factors was observed in the controls. Multivariable regression showed risk factors of secondary infections included male (OR 4.08; 95% CI 1.58-10.50), age 65 or older (OR 3.11; 95% CI 1.25-7.76), heart diseases (OR 3.96; 95% CI 1.40-11.27), hypoproteinemia on admission (OR 6.41; 95% CI 1.65-24.92) and corticosteroids (OR 19.83; 95% CI 7.3-53.55) and proton-pump inhibitors (OR 3.96; 95% CI 1.51-10.37).Conclusions: male, older age, heart diseases, hypoproteinemia, corticosteroid and proton-pump inhibitors were independent risk factors of secondary infections. Inpatients needing ICU admission and invasive devices still need to be given optimal cares and to be minimized the duration.