Objective: Insulin receptor substrates type 1 and 2 polymorphisms(IRS-1 Gly972Arg and IRS-2 Gly1057Asp may play a functional role on the insulin-resistant component of PCOS. The present study was therefore undertaken with a pilot manner to study the frequency of IRS1Gly972Arg and IRS2 Gly1057Asp polymorphisms and compare the prevalence of these two polymorphisms in PCO patients and non-diabetic healthy women in Iranian subjects. Materials and Methods: Forty eight PCO patients were participated in our study. Fifty two non-diabetics, non-PCO women referred to our clinic for non-PCOS related infertility workup were randomly collected as control group. All individuals had an oral glucose tolerance test. Results: Frequencies of IRS-1Gly972Arg variants were shown to be 92.3% for Gly/Gly, 7.7% for Gly/Arg and within control subjects and 91.7% for Gly/Gly, 6.2% for Gly/Arg and 2.1% for Arg/Arg within PCOS patients. For IRS-2Gly1057Asp, frequency of variants were 46.2% for Gly/Gly, 46.2% for Gly/Asp and 7.7% for Asp/Asp within control subjects and 43.3% for Gly/Gly, 37.5% for Gly/Asp and 18.8% for Asp/Asp within PCOS patients, where no statistically significant difference were detected. Moreover, no association was observed when considering the combination of both polymorphisms. Control subjects with the IRS-1 Gly/Arg genotype had higher levels of glucose at 2 hours during the OGTT (91.9 ± 11.9 mg/dL) compared with those with the Gly/Gly (107 ± 14 mg/dL; p = 0.037) genotype. To compare the clinical and metabolic characteristics of IRS-2 alleles, we grouped Gly/Asp and Asp/Asp alleles as a single group and compared it with wild type Gly/Gly allele. Comparing variables in whole control subjects and PCOS patients, we didn’t find any statistical significant difference within. after excluding non-over weight subjects (BMI≤25), wild type over weight control subjects revealed to have higher post prandial blood sugar comparing with mutated over weight subjects (98.7 ± 12.1 vs 87 ± 13.5 ; p = 0.02) and BMI of over weight PCOS patients with wild type genotype (27.8 ± 3.8) and mutated genotype (31.1 ± 5) differed (p = 0.008). Conclusion: In conclusion, considering that no association between the IRS-1 Gly972Arg and IRS-2 Gly1057Asp polymorphisms and PCOS were found, our present results confirm that these polymorphisms should not be considered as major contributors to the pathogenesis of this disorder. Furthermore IRS-1 Gly972Arg could be considered as a risk factor and IRS-2 Gly1057Asp could be mentioned as a supportive mutation in overweight/obese subjects against PPBS increase. Also IRS-2 polymorphism might influence the phenotypic characteristics of overweight/obese PCOS patients.