Based on the premise that oxidative stress plays an important role in severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection, we speculated that variations in the antioxidant activities of different members of the glutathione S-transferase family of enzymes might modulate individual susceptibility towards development of clinical manifestations in COVID-19. The distribution of polymorphisms in cytosolic glutathione S-transferasesGSTA1,GSTM1,GSTM3,GSTP1(rs1695andrs1138272), andGSTT1were assessed in 207 COVID-19 patients and 252 matched healthy individuals, emphasizing their individual and cumulative effect in disease development and severity.GSTpolymorphisms were determined by appropriate PCR methods. Among sixGSTpolymorphisms analyzed in this study,GSTP1rs1695 andGSTM3were found to be associated with COVID-19. Indeed, the data obtained showed that individuals carrying variantGSTP1-Valallele exhibit lower odds of COVID-19 development (p = 0.002), contrary to carriers of variantGSTM3-CCgenotype which have higher odds for COVID-19 (p = 0.024). Moreover, combinedGSTP1(rs1138272andrs1695) andGSTM3genotype exhibited cumulative risk regarding both COVID-19 occurrence and COVID-19 severity (p = 0.001 andp = 0.025, respectively). Further studies are needed to clarify the exact roles of specific glutathione S-transferases once the SARS-CoV-2 infection is initiated in the host cell.