BackgroundClinical severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outcomes could be influenced by genetic polymorphisms in angiotensin I-converting enzyme (ACE1) andACE2. This study aims to examine three polymorphisms (rs1978124, rs2285666, and rs2074192) on theACE2gene andACE1rs1799752 (I/D) in patients who have coronavirus disease 2019 (COVID-19) with various SARS-CoV-2 variants.MethodsBased on polymerase chain reaction-based genotyping, four polymorphisms in theACE1andACE2genes have been identified in 2023 deceased patients and 2307 recovered patients.ResultsTheACE2rs2074192 TT genotype was associated with the COVID-19 mortality in all three variants, whereas the CT genotype was associated with the Omicron BA.5 and Delta variants.ACE2rs1978124 TC genotypes were related to COVID-19 mortality in the Omicron BA.5 and Alpha variants, but TT genotypes were related to COVID-19 mortality in the Delta variant. It was found thatACE2rs2285666 CC genotypes were associated with COVID-19 mortality in Delta and Alpha variants, and CT genotypes in Delta variants. There was an association betweenACE1rs1799752 DD and ID genotypes in the Delta variant and COVID-19 mortality, whereas there was no association in the Alpha or Omicron BA.5 variants. In all variants of SARS-CoV-2, CDCT and TDCT haplotypes were more common. In Omicron BA.5 and Delta, CDCC and TDCC haplotypes were linked with COVID-19 mortality. In addition to COVID-19 mortality, the CICT, TICT, and TICC were significantly correlated.ConclusionTheACE1/ACE2polymorphisms had an impact on COVID-19 infection, and these polymorphisms had different effects in various SARS-CoV-2 variants. To confirm these results, however, more research needs to be conducted.Supplementary InformationThe online version contains supplementary material available at 10.1186/s40246-023-00501-8.