Early identification of potential risk factors and timely intervention, are crucial for reducing the rates of severe illness and mortality. As such, there is a pressing need to focus more on the care of severe patients and reduce the mortality rate associated with SARS-CoV-2. Given that older patients are a vulnerable demographic, comprehensive data is required to enhance their healthcare provision in the context of the COVID-19 pandemic. The unprecedented pandemic from November 2022 to January 2023 provided us with valuable clinical resources on older patients, a demographic that has been underrepresented in past studies. Mass spectrometry (MS)-based proteomics enables the systematic investigation of circulating proteins which sheds light on host responses to SARS-COV-2 infection. Here, we report the characteristic proteome profile of plasma samples from elderly patients with Omicron infection, with a primary focus on features associated with mortality.