Polycystic ovary syndrome (PCOS) is the most common and a complex female endocrine disorder, and is one of the leading cause of female infertility. Here, we aimed to investigate the association of single-nucleotide polymorphism of INS, INSR, IRS1, IRS2, PPAR-G and CAPN10 gene in the pathogenesis of PCOS. A hospital-based, observational case-control study was carried on 169 PCOS and 169 control women in the southern region of India. Genotype was carried out by real-time polymerase chain reaction. A chi-square (χ2) test was performed and the genotypes were verified to comply with the Hardy- Weinberg equilibrium. Odds ratio and 95% confidence interval were calculated to assess the relative risk. Comparison of clinical characteristics of women with PCOS and controls reveal an increase in body mass index (BMI), luteinizing hormone / follicle stimulating hormone (LH/FSH) ratio, glucose levels, insulin, testosterone, hirsutism and antral follicular count in PCOS women. The variant rs1801278 (P = 0.002; OR = 2.88; 95% CI = 1.43, 5.80) show an association with PCOS. In the genotypic (P = 0.0002) and allelic models (P = 0.000), significance persisted even after Bonferroni correction. The genotypes of SNPs strongly influence BMI, LH, LH/FSH ratio, ovarian volume and antral follicular count in PCOS women. The study results were suggestive of a positive association between Gly972Arg of IRS1 and PCOS in the south Indian population, while INS, IRS2, PPAR-G and CAPN10 failed to show any association with PCOS in our studied population. Further studies focussing the role of IRS1 are warranted to delineate its implication towards PCOS.