AbstractAccumulating data has shown a contribution of the renin‐angiotensin system in COVID‐19 pathogenesis. The role of angiotensin‐converting enzyme (ACE) insertion (I)/deletion (D) polymorphism as a risk factor in developing COVID‐19 disease comes from epidemiological data and is controversially discussed. We conducted a retrospective case‐control study and assessed the impact of ACE I/D genotype in COVID‐19 disease prevalence and severity. In 81 COVID‐19 patients explicitly characterized and 316 controls, recruited during the first wave of COVID‐19 pandemic, ACE I/D genotype, and ACE activity were determined. A generalized linear model was used and Poisson regression analysis estimated the risk ratios (RRs) of alleles and genotypes for disease severity. DD patients had almost 2.0‐fold increased risk (RR: 1.886, confidence limit [CL] 95%: 1.266–2.810, p = 0.0018) of developing a more severe disease when contrasted to ID and II individuals, as did D allele carriers compared to I carriers (RR: 1.372; CL 95%: 1.051–1.791; p = 0.0201). ACE activity (expressed as arbitrary units, AU/L) was lower in patients (3.62 ± 0.26) than in controls (4.65 ± 0.13) (p < 0.0001), and this reduction was observed mainly among DD patients compared to DD controls (3.97 ± 0.29 vs. 5.38 ± 0.21; p = 0.0014). Our results demonstrate that ACE DD genotype may predispose to COVID‐19 increased disease severity via a mechanism associated, at least in part, with the significant fall in their ACE activity. Our findings suggest a more complex pattern of synergy between this polymorphism and ACE activity in COVID‐19 patients compared to healthy individuals and set the grounds for large‐scale studies assessing ACE genotype‐based optimized therapies with ACE inhibitors and angiotensin receptor blockers.