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Although advanced age, male sex, and some comorbidities impact the clinical course of COVID-19, these factors only partially explain the inter-individual variability in disease severity. Some studies have shown that genetic polymorphisms contribute to COVID-19 severity; however, the results are inconclusive. Thus, we investigated the association between polymorphisms in ACE1 , ACE2 , DPP9 , IFIH1 , IFNAR2 , IFNL4 , TLR3 , TMPRSS2 , and TYK2 and the clinical course of COVID-19. A total of 694 patients with COVID-19 were categorized as: (1) ward inpatients (moderate symptoms) or patients admitted at the intensive care unit (ICU; severe symptoms); and (2) survivors or non-survivors. In females, the rs1990760/ IFIH1 T/T genotype was associated with risk of ICU admission and death. Moreover, the rs1799752/ ACE1 Ins and rs12329760/ TMPRSS2 T alleles were associated with risk of ICU admission. In non-white patients, the rs2236757/ IFNAR2 A/A genotype was associated with risk of ICU admission, while the rs1799752/ ACE1 Ins/Ins genotype, rs2236757/ IFNAR2 A/A genotype, and rs12329760/ TMPRSS2 T allele were associated with risk of death. Moreover, some of the analyzed polymorphisms interact in the risk of worse COVID-19 outcomes. In conclusion, this study shows an association of rs1799752/ ACE1 , rs1990760/ IFIH1 , rs2236757/ IFNAR2 , rs12329760/ TMPRSS2 , and rs2304256/ TYK2 polymorphisms with worse COVID-19 outcomes, especially among female and non-white patients.