Natural killer (NK) cells play a key role in the innate immune response against viral infections. Their activity is regulated by a balance of activating and inhibitory signals, which are modulated by interactions with HLA class I molecules, including HLA-E. The HLA-B 21M/T dimorphism influences the availability of HLA-B leader peptides that stabilize HLA-E expression and modulate NK cell function via the NKG2A/CD94 receptor. To investigate the association between the HLA-B –21M/T dimorphism and the clinical severity of COVID-19, we analyzed a cohort of hospitalized patients with primary SARS-CoV-2 infection, who were genotyped for the HLA-B –21M/T dimorphism. Clinical data, lymphocyte counts, the neutrophil-to-lymphocyte ratio (NLR), and inflammatory markers were compared across genotypes. Contrary to previous studies suggesting a protective effect of the M/M genotype, we found no significant association between the HLA-B –21M/T dimorphism and COVID-19 severity, lymphocyte parameters, or inflammatory biomarkers. Our findings do not support a role for the HLA-B –21M/T dimorphism in modulating COVID-19 outcomes. These results underscore the complexity of NK cell regulation and highlight the need for integrative studies combining genetic, immunological, and functional data to better understand host factors influencing disease progression.