The objectives of this study were to (1) investigate the association between human blood type and COVID-19 in both inpatient and longitudinal populations and (2) identify the association between blood type and severity of COVID-19 via presence of cellular biomarkers of severe infection in hospitalized individuals at our institution in South Florida. This study consisted of (1) a single-center retrospective analysis of 669 out of 2741 COVID-19-positive, screened patients seen from 1 January 2020 until 31 March 2021 at the University of Miami Emergency Department (ED) who tested positive for COVID-19 and had a documented ABO blood type and (2) a longitudinal SARS-CoV-2 immunity study (“CITY”) at the University of Miami Miller School of Medicine, consisting of 185 survey participants. In an inpatient setting, blood type appeared to be associated with COVID-19 severity and mortality. Blood type O sustained less risk of COVID-19 mortality, and blood type O- demonstrated less risk of developing COVID-19 pneumonia. Inpatients with O- blood type exhibited less biomarkers of severe infection than did other blood types. In a longitudinal setting, there was no association found between blood type and SARS-CoV-2 infection.