Oxidative stress may play a role in the recurrent miscarriage (RM) with no known etiology. This study was conducted to investigate the association of polymorphisms in oxidative stress-related genes with idiopathic RM. A total of 331 idiopathic RM patients and 197 controls were genotyped for ABCB1 rs1045642, CYP1A1 rs1048943 and rs4646903, COMT rs4680, CAT rs17880664, GCLC rs17883901, GPX4 rs713041, NRF2 rs6721961, SOD2 rs4880, and OGG1 rs1052133. A protective effect of COMT rs4680-G allele on RM was shown in individual SNP analysis: P = 0.0016, OR = 0.47, 95% CI 0.29-0.75. The multi-factor dimensionality reduction (MDR) approach revealed gene-gene interactions for ABCB1, COMT, GPX4, and OGG1 genes. Cumulative gene risk score analysis demonstrated that more than three risk alleles in the genes ABCB1 (rs1045642-T), COMT (rs4680-A), GPX4 (rs713041-T), and OGG1 (rs1052133-G) were associated with idiopathic RM P = 1.2 × 10(-3), OR = 1.97, 95% CI 1.31-2.97. In silico data interpreting by GeneMANIA analysis revealed genetic, physical, pathway, and coexpression networks for these four genes.