Abstract Background There has been uncertainty about the safety or benefit of angiotensin-converting enzyme (ACE) inhibitors during the COVID-19 pandemic. We used Mendelian randomization using genetic determinants of serum-ACE levels to test whether decreased ACE levels increase susceptibility to SARS-CoV-2 infection or COVID-19 severity, while reducing potential bias from confounding and reverse causation in observational studies. Methods Genetic variants strongly associated with ACE levels, which were nearby the ACE gene, were identified from the ORIGIN trial and a separate genome-wide association study (GWAS) of ACE levels from the AGES cohort. The ORIGIN trial included 4147 individuals of European and Latino ancestries. Sensitivity analyses were performed using a study of 3200 Icelanders. Cohorts from the COVID-19 Host Genetics Initiative GWAS of up to 960 186 individuals of European ancestry were used for COVID-19 susceptibility, hospitalization and severe-disease outcome. Results Genetic variants were identified that explain between 18% and 37% of variance in ACE levels. Using genetic variants from the ORIGIN trial, a standard-deviation decrease in ACE levels was not associated with an increase in COVID-19 susceptibility [odds ratio (OR): 1.02, 95% confidence interval (CI): 0.90, 1.15], hospitalization (OR: 0.86, 95% CI: 0.68, 1.08) or severe disease (OR: 0.74, 95% CI: 0.51, 1.06). Using genetic variants from the AGES cohort, the result was similar for susceptibility (OR: 0.98, 95% CI: 0.89, 1.09), hospitalization (OR: 0.86, 95% CI: 0.66, 1.11) and severity (OR: 0.75, 95% CI: 0.50, 1.14). Multiple-sensitivity analyses led to similar results. Conclusion Genetically decreased serum ACE levels were not associated with susceptibility to, or severity of, COVID-19 disease. These data suggest that individuals taking ACE inhibitors should not discontinue therapy during the COVID-19 pandemic.