Background. Several reports have related renin-angiotensin system impairment to the severity of COVID-19 and other pulmonary disorders. Aims. To evaluate the association of the rs1799752 variant in the ACE gene and the serum ACE enzyme activity with the severity of COVID-19. Methods. We evaluated 1,252 patients with severe COVID-19; 104 subjects recovered from COVID-19 who were hospitalized and required invasive mechanical ventilation (IMV) (post-COVID-19 patients); and 74 patients hospitalized due to a chronic respiratory disease different to COVID-19 diagnosis (non-COVID-19 patients). The rs1799752 indel variant (I/D) was genotyped using TaqMan Assays. The serum ACE activity was determined in a subgroup of patients (n=161) employing the ACE Activity Assay Kit (Colorimetric, Abcam). Data analyses were performed in PLINK and RStudio. Results. We found a higher frequency of the DD genotype among patients that required IMV when compared to non-IMV subjects following a recessive model (p=0.025, OR=1.43, 95% CI 1.05-1.95); meanwhile, the ID genotype was associated with a decreased risk of IMV (p=0.005, OR=0.70, 95% CI 0.55-0.90). Moreover, the frequency of this genotype was higher in patients with COVID-19 (p=0.031) and post-COVID-19 (0.025) than those included in the non-COVID-19 group. The serum ACE activity level was found to be higher for the post-COVID-19 (50.00 U/L [42.16-62.25 U/L]) when compared to non-COVID-19 (22.30 U/L [13.84-32.23 U/L]) and COVID-19 groups (27.94 U/L [20.32-53.36 U/L]). Conclusion. The DD genotype confers a risk of IMV in patients with COVID-19; meanwhile, a decreased serum ACE activity level could be related to severe COVID-19.