Objective: To investigate the frequency of glutathione S-transferase (GST), catalase, and SOD2 genetic polymorphisms and their correlation with SLE. Methods: A total of 290 females (patients = 151; controls= 139) were recruited. Multiplex PCR was performed for genotyping GSTM1 and GSTT1 genes, whereas real-time qPCR was used for determination of SNPs: CAT C262T, SOD2 C47T, GSTP1 A313G and GSTP1 IVS6 -C16T. Results: Thiol levels are decreased in SLE patients (p<0.001), while MDA levels were significantly higher (p<0.001) and those carrying the polymorphisms had higher rates of oxidative stress. Patients with double null deletion GSTT1null/GSTM1null had a frequency almost five times higher than the controls (p<0.001, OR 4.81, CI 1.98–12.11). SLE patients had a lower wild-type frequency of SOD2CC allele compared to controls (12.4% vs 27.3%). Statistical significances were observed on the association between the GSTT1null and GSTM1null with SOD2mut (p<0.001, OR 0.15, CI 0.05–0.47), with GSTP1 A303G (p=0.012, OR 0.19, CI 0.05–0.69), and with GSTP1 IVS6 (p=0.008, OR 0.14, CI 0.03–0.63). The same was observed between SOD2 C47T with GSTP1 A303G (p=0.09, OR 0.27, CI 0.09–0.74) and GSTP1 IVS6 (p=0.036, OR 0.41, CI 0.18–0.92). Conclusions: The deletion GSTT1null/GSTM1null may contribute to the increased of the oxidative stress in SLE patients. Isolated GSTP1 and CAT polymorphisms do not seem to influence the increased oxidative stress, neither SLE clinical manifestations. SOD2 47CT/TT allele may have greater oxidative stress due to structural change in the protein and decreased H2O2 production. The combination of polymorphic genes may be involved in the pathogenesis of the disease.