Background: Polycystic ovary syndrome (PCOS) is a leading cause of infertility. Insulin resistance is a key element in pathogenesis. The insulin receptor causes phosphorylation of the insulin receptor substrate (IRS); IRS-1 rs1801278G > A polymorphism variant is the most common genetic variant associated with IR and PCOS. Objective: We aimed to examine the frequency of IRS-1 rs1801278G > A polymorphism variant and test its value in evaluating infertile PCOS women. Methods: A case-control study recruited 140 age and body-mass-matched participants in the university hospital, subdivided according to Rotterdam criteria into PCOS cases (70/140) and healthy controls (70/140). We collected demographic data, ultrasonic [antral follicles and endometrial thickness], hormonal [FSH, LH, AMH, E2], and genetic data by polymerase chain reaction for analysis. Result: Wild GG SNP rs1801278 G was meaningfully higher among controls (58.57%, P<0.0001). Mutant AA SNP rs1801278 was significantly higher in PCOS women (37.14%, P-value =0.0001, an odds ratio of 20.50, 95% CI (9.42-28.63) to develop PCOS. Heterogenous GA gene SNP rs1801278 showed a trend of higher frequency in PCOS patients with 44.29%; OR of 3.91, 95% CI (1.37–7.55); P = 0.422. Upon correlating infertility parameters to SNP rs1801278 G>A polymorphism, statistical differences were found with AFC, LH/FSH ratio, and serum testosterone. As for the AMH, E2, and endometrial thickness, they failed to have a statistical value. Conclusion: The significant correlation of genetic polymorphism to infertility parameters among PCOS women opens a new therapeutic and prognostic avenue that helps gynecologists tailor manganate for a better and safer outcome.