Background: The variation in clinical outcomes among those with severe acute respiratory syndrome caused by coronavirus 2 increased the urgency to identify the pathophysiological characteristics of this disease. Clinical results may be impacted by genes implicated in antiviral defence systems and inflammatory organ damage, particularly the HLA system that is essential for the immunological response. Objective: Our aim was to determine the HLA-A and -B genotypes of 60 Egyptian COVID-19 cases and connect those findings with illness results, clinical information, and laboratory data. Patients and methods: A total of 60 Egyptian COVID-19 cases were consecutively recruited from Ain Shams University Hospitals. Only, confirmed cases of SARS-CoV-2 with positive nasopharyngeal swab by real-time RT-PCR were involved in the research. Patients with negative PCR for COVID-19, were neglected. Results: We found that allele B*41 and A*01 were associated with COVID-19 susceptibility. Whereas allele B*35 was associated with disease severity. The analysis of risk variables using a multivariate regression model revealed that HLA-B*33 was connected to anticipated protection against mortality. Patient survival was affected by increased age, associated comorbidities, high CRP, and elevated serum creatinine. Conclusion: We concluded that individual HLA class I (A&B) genotypes can affect the association and the severity of COVID-19 and even the protection; through immune response modulation, which might aid physicians in deciding what medical care is most important and greatly reduce COVID-19 mortality.