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Mutations associated with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) resistance to antiprotease nirmatrelvir were reported. We aimed to detect them in SARS‐CoV‐2 genomes and quasispecies retrieved in our institute before drug availability in January 2022 and to analyze the impact of mutations on protease (3CLpro) structure. We sought for 38 3CLpro nirmatrelvir resistance mutations in a set of 62 673 SARS‐CoV‐2 genomes obtained in our institute from respiratory samples collected between 2020 and 2023 and for these mutations in SARS‐CoV‐2 quasispecies for 90 samples collected in 2020, using Python. SARS‐CoV‐2 protease with major mutation E166V was generated with Swiss Pdb Viewer and Molegro Molecular Viewer. We detected 22 (58%) of the resistance‐associated mutations in 417 (0.67%) of the genomes analyzed; 325 (78%) of these genomes had been obtained from samples collected in 2020−2021. APOBEC signatures were found for 12/22 mutations. We also detected among viral quasispecies from 90 samples some minority reads harboring any of 15 nirmatrelvir resistance mutations, including E166V. Also, we predicted that E166V has a very limited effect on 3CLpro structure but may prevent drug attachment. Thus, we evidenced that mutations associated with nirmatrelvir resistance pre‐existed in SARS‐CoV‐2 before drug availability. These findings further warrant SARS‐CoV‐2 genomic surveillance and SARS‐CoV‐2 quasispecies characterization. [ABSTRACT FROM AUTHOR]