Our data demonstrated that the most common investigated mtDNA variants (> 10% in the control population) at C5178a (ND2) and A249d (D-loop)/T6392C (CO1)/G10310A (ND3) contributed to an individual’s resistance to developing severe COVID-19, whereas A4833G (ND2), A4715G (ND2), T3394C (ND1) and G5417A (ND2)/C16257a (D-loop)/C16261T (D-loop) polymorphisms increased the risk of severe COVID-19 in this population. The gene discussed is MT-ND3; the disease is COVID-19.