Background: A common polymorphism (677C to T; Ala to Val) in the methylenetetrahydrofolate reductase (MTHFR) gene is associated with decreased specific MTHFR activity and elevation of homocysteine. The present study aimed to investigate the association between a single nucleotide polymorphism (SNP) in the MTHFR 677C>T gene and insulin resistance in women with polycystic ovary syndrome (PCOS). Methods: Two‐hundred patients with PCOS were included in this case–control study: 100 patients with insulin resistance and 100 patients without insulin resistance were genotyped by polymerase chain reaction–restriction fragment length polymorphism analysis. Results: The TT genotype for the MTHFR 677C>T polymorphism was significantly more frequent in PCOS patients with insulin resistance than in PCOS patients without insulin resistance (19% versus 6%, p = 0.002), whereas there was no significant difference between both groups for CT and there was a statistically significant increase in the T allele in PCOS patients with insulin resistance compared to PCOS patients without insulin resistance (p = 0.002, odds ratio = 1.95 and 95% confidence interval =( 1.29‐2.93). Regarding the relationship between MTHFR 677C>T genotypes and the characteristics of insulin resistance in PCOS patients, we found that there was no significant difference in age, waist‐hip ratio and total testosterone between the different genotypes of the MTHFR 677C>T polymorphism. The mean values for body mass index and the Homeostatic Model Assessment of Insulin Resistance were significantly higher in the TT genotype of MTHFR 677C>T compared to the CC genotype in PCOS patients with insulin resistance (p < 0.001). Conclusions: We have demonstrated an association of the MTHFR 677C>T gene polymorphism with insulin resistance in Egyptian women with PCOS.