The global pandemic of COVID-19, caused by the novel coronavirus SARS-CoV-2, has resulted in widespread alterations to public health measures worldwide. This observational study aimed to assess the clinical features and results of respiratory failure in patients with severe COVID-19. A single-center observational study was performed at a Chinese hospital between November 1, 2022, and February 31, 2023. All 182 enrolled patients were diagnosed with respiratory failure, 84 patients were infected with COVID-19, and the other 98 patients were not infected. A review of available medical records at admission and discharge, including neuroimaging, laboratory values at admission, mortality, length of hospitalization, and hospital costs, was conducted during the COVID-19 pandemic. All 182 eligible patients completed the follow-up. There was no significant difference in baseline characteristics between respiratory failure combined with COVID-19 (P > .05). Respiratory failure combined with COVID-19 infection may lead to higher 30-day mortality (16.36% vs 7.14%, P = .005), longer hospital stays (22.5 ± 5.9 vs 12.8 ± 4.2, P < .001), larger hospitalization costs (P < .001), and increased hospitalization complications, such as pulmonary embolism (10.30% vs 4.76%, P = .039), deep vein thrombosis (33.33% vs 18.57%, P = .001), incidence of 7-day delirium (69.70% vs 46.19%, P < .001), and respiratory failure (38.18% vs 24.77%, P = .005). If respiratory failure occurs while the patient is infected with COVID-19, treatment and prognosis worsen. Our understanding of COVID-19 and the care we provide to patients with respiratory failure is crucial to better prepare for a potential pandemic.