Abstract Patients infected with SARS-CoV-2 may show mild infection or may develop severe coronavirus disease 2019 (COVID-19). In the present study, we investigated whether there is an association between the severity of COVID-19 and the naturally occurring human genetic variants in the natural killer (NK) cell NKG2C receptor (NKG2Cwt/del) and its cellular ligand HLA-E (HLA-E*0101/0103). Both factors are essential components of the NKG2C+ NK cell response and important parts of the defence against pulmonary viral infection. NKG2Cdel and HLA-E*0101 were significantly overrepresented in hospitalized patients (p=0.0006 and p=0.01, respectively) and particularly in critically ill patients requiring intensive care (p<0.0001 and p=0.01, respectively), compared to patients with mild symptoms or healthy controls. Both genetic variants were found to be independent risk factors for severe COVID-19. The data highlight that specific NKG2C+ NK cell responses play an important role against SARS-CoV-2 and that variations thereof may significantly influence the severity of disease.