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Human polymorphisms may contribute to SARS-CoV-2 infection susceptibility and COVID-19 outcomes (asymptomatic presentation, severe COVID-19, death). We aimed to evaluate the association of IFITM3, FURIN, ACE1, and TNF-α genetic variants with both phenotypes using meta-analysis. The bibliographic search was conducted on the PubMed and Scielo databases covering reports published until February 8, 2022. Two independent researchers examined the study quality using the Q-Genie tool. Using the Mantel–Haenszel weighted means method, odds ratios were combined under both fixed- and random-effect models. Twenty-seven studies were included in the systematic review (five with IFITM3, two with Furin, three with TNF-α, and 17 with ACE1) and 22 in the meta-analysis (IFITM3 n = 3, TNF-α, and ACE1 n = 16). Meta-analysis indicated no association of 1) ACE1 rs4646994 and susceptibility, 2) ACE1 rs4646994 and asymptomatic COVID-19, 3) IFITM3 rs12252 and ICU hospitalization, and 4) TNF-α rs1800629 and death. On the other hand, significant results were found for ACE1 rs4646994 association with COVID-19 severity (11 studies, 692 severe cases, and 1,433 nonsevere controls). The ACE1 rs4646994 deletion allele showed increased odds for severe manifestation (OR: 1.45; 95% CI: 1.26–1.66). The homozygous deletion was a risk factor (OR: 1.49, 95% CI: 1.22–1.83), while homozygous insertion presented a protective effect (OR: 0.57, 95% CI: 0.45–0.74). Further reports are needed to verify this effect on populations with different ethnic backgrounds.Systematic Review Registration: https://www.crd.york.ac.uk/prosperodisplay_record.php?ID=CRD42021268578, identifier CRD42021268578