Background/Objectives: The COVID-19 pandemic has highlighted the importance of identifying factors influencing disease susceptibility and severity. This study investigates the association of ABO blood groups, the D antigen, and comorbidities such as hypertension and diabetes with COVID-19 severity among hospitalized patients in one Croatian center. Methods: A retrospective observational study was performed on 1687 moderately and severely ill COVID-19 patients and 7086 voluntary blood donors. We used medical records from PCR-confirmed COVID-19 patients hospitalized at University Hospital Center Osijek in Osijek, Croatia, and compared their ABO, RhD, and comorbidity profiles with those of voluntary blood donors. Key clinical data and outcomes, such as mortality and comorbidities, were assessed. Results: Our findings reveal a statistically significant association between blood group A and severe COVID-19 outcome and mortality. Conversely, D antigen status showed no significant impact. The combined presence of hypertension and diabetes emerged as a significant predictor of mortality. Conclusions: These results suggest that blood group A and specific comorbidities may be associated with worse outcomes, but age remained the strongest independent predictor of mortality. Blood group typing could still support risk stratification when interpreted alongside other clinical factors.