Background <p>Despite high vaccination rates, severe and critical illnesses in hospitalized patients with COVID-19 continue to pose significant challenges to healthcare systems. This study aimed to identify factors associated with mortality among hospitalized patients with COVID-19 who had received three vaccine doses during the spread of the SARS-CoV-2 Omicron variant.</p> Methods <p>This retrospective observational study was conducted at the Taipei Veterans General Hospital between April and June 2022. Hospitalized adult patients with confirmed COVID-19 who had received three vaccine doses before diagnosis were included. Demographic data, comorbidities, disease severity indicators, laboratory values, and treatment details were collected from the electronic records. Logistic regression analysis was used to identify the factors associated with 28-day mortality and the need for invasive mechanical ventilation.</p> Results <p>A total of 620 patients with a median age of 75 years were hospitalized for COVID-19, and the 28-day mortality rate was 7.9%. The independent predictors of mortality included a higher comorbidity burden, elevated World Health Organization (WHO) ordinal scale scores, elevated neutrophil-to-lymphocyte ratios (NLR), and thrombocytopenia. Among the 610 initially non-ventilated patients, 6.6% required invasive mechanical ventilation. Hematological malignancy, metastatic cancer, higher WHO ordinal scales, elevated NLR and bacterial secondary infection were significant risk factors for respiratory failure.</p> Conclusion <p>Despite receiving three doses of the COVID-19 vaccines, patients hospitalized with COVID-19 continue to experience notable rates of mortality and respiratory failure. During the current endemic phase of COVID-19, these prognostic indicators can help guide the management and early intervention of high-risk patients.</p>