Our analyses of ACE rs4646994 shows that rs4646944 is associated with lower risk of COVID-19 in heterozygous (OR = 0.35, 95%CI = 0.23–0.52, p < 0.001, ID vs DD), homozygous (OR = 0.23, 95%CI = 0.13–0.41, p < 0.001, II vs DD), dominant (OR = 0.31, 95%CI = 0.21–0.46, p < 0.001, ID+DD vs DD), recessive (OR = 0.40, 95%CI = 0.24–0.67, p < 0.001, II vs ID+II), and overdominant (OR = 0.51, 95%CI = 0.36–0.74, p < 0.001, ID vs DD + II) models increased the risk of COVID-19 infection. This evidence concerns the gene ACE and COVID-19.