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Introduction: The novel coronavirus causes the deadly disease, severe acute respiratory syndrome (SARS). Therefore, it is necessary to identify prognostic factors for patients hospitalized with SARS-coronavirus-2 infection to identify patients with increased mortality risk. Several studies have shown that polymorphisms within the ABO gene are associated with different traits, including risk factors for coronavirus disease 2019 (COVID-19) mortality. Methods: We conducted a prospective, single-center study at the Pulmonologist Department of Rouiba Hospital, Algiers. The medical records of 498 COVID-19 patients enrolled in this cohort study were hospitalized between March 2020 and March 2022. The patient reported the blood group (grouping card) or was carried out on site. The patients were divided into 10 groups: A+, A−, B+, B−, O+, O−, AB+, AB−, (Rhesus+ABO/Rh blood groups), and Rhesus-groups, according to the distribution of ABO blood group. The different ABO blood group of the 498 patients was analyzed and compared according to their prognosis, death, or transfer to an intensive care unit. Results: Four hundred and ninety-eight patients were evaluated, 213 (42.8%) were male, and the mean age was 55.2 years (standard deviation: 15.3). A total of 473 (94.98%) patients were discharged, and 25 (5.02%) died during hospitalization. The number of patients with ARh negative was significantly higher in the dead patients 30% among 10 patients (P = 0.0002) versus 5.6% for A+, compared to improved individuals and more computed tomography scan lesion extension 40% (P = 0.021) between 50% and 75% vs. 13.2% ± 34.0% (P = 0.034) for the A(+) group, and hypernatremia 141.2 ± 2.7 (P = 0.056) versus 137.4 ± 4.36 for A(+) group. The distribution of ABO blood groups was statistically different between the two groups. The dead patients had the blood groups A(−), (30%), A+ (5.6%), B− (0%), B+ (1.5%), AB− (0%), AB+ (0%), O− (20%), and O+ (4.3%), respectively. Conclusion: The protective nature of all blood groups (AB, B, and O+) was observed in patients presenting with COVID-19 symptoms of varying severities. Blood grouping A and especially A− and O− are marked by a high risk of COVID-19 infection, serious form, and mortality and therefore deserve particular attention in their management.