Background and Objectives: Severe COVID-19 still constitutes an important health problem. Taking into account the crucial role of HLA in immune reactions, evaluation of the impact of HLA on COVID-19 risk and clinical course seemed necessary, as the already available data are inconsistent. The aim of the present study was to compare the HLA profiles of patients with symptomatic SARS-CoV-2 infection and a healthy control group, as well as to compare HLA allele frequencies in patients with severe and non-severe courses of COVID-19. Materials and Methods: HLA classes were genotyped using a next-generation sequencing method in 2322 persons, including 2217 healthy hematopoietic stem cell potential donors and 105 patients with symptomatic COVID-19. Results: Symptomatic course of SARS-CoV-2 infection appeared to be associated with the presence of HLA-A*30:01, B*44:02, B*52:01, C*05:01, C*17:01, and DRB1*11:02, while HLA-C*07:04 and DQB1*03:03 seem to play a protective role. Moreover, we demonstrated that the severe symptomatic course of COVID-19 can be associated with the presence of HLA-B*08:01, C*04:01, DRB1*03:01, and DQB1*03:01, while HLA-DRB1*08:01 appeared to be protective against severe COVID-19 disease. Conclusions: Identification of alleles that are potentially associated with symptomatic SARS-CoV-2 infection as well as the severe course of COVID-19 broadens the knowledge on the genetic background of COVID-19 course and can constitute an important step in the development of personalized medicine.