Abstract Background HLA class I molecules play a crucial role in the development of a specific immune response to viral infections by presenting viral peptides to cell surface where they will be further recognized by T cells. In the present manuscript we explored whether HLA class I genotype can be associated with critical course of COVID-19 by searching possible connections between genotypes of deceased patients and their age at death. Methods and Findings HLA-A, HLA-B and HLA-C genotypes of n = 111 deceased patients with COVID-19 (Moscow, Russia) and n = 428 volunteers were identified with targeted next-generation sequencing. Deceased patients were splitted into two groups according to age at death: n = 26 adult patients with age at death below 60 completed years (inclusively) and n = 85 elderly patients over 60. With the use of HLA class I genotypes we developed a risk score which is associated with the ability to present SARS-CoV-2 peptides by an individual’s HLA class I molecule set. The resulting risk score was significantly higher in the group of deceased adults compared to elderly adults (p = 0.00348, AUC ROC = 0.68). In particular, presence of HLA-A*01:01 allele was associated with high risk, while HLA-A*02:01 and HLA-A*03:01 mainly contributed to the low risk group. The analysis of homozygous patients highlighted the results even stronger: homozygosity by HLA-A*01:01 mainly accompanied early deaths, while only one HLA-A*02:01 homozygote died before 60. Conclusions The obtained results suggest the important role of HLA class I peptide presentation in the development of a specific immune response to COVID-19. While prediction of age at death by HLA class I genotype had a reliable performance, involvement of HLA class II genotype can make it even higher in the future studies.