To investigate the role of IRS1 locus on failure to oral antidiabetes drugs (OADs) we genotyped single-nucleotide polymorphisms (SNPs), rs2943641, rs7578326 (tagging all SNPs genome-wide associated with type 2 diabetes (T2D) and related traits at this locus) and rs1801278 (that is, the loss-of-function IRS1 G972R amino acid substitution) in 2662 patients with T2D. Although no association with OAD failure was observed for rs2943641 and rs7578326 SNPs (odds ratio (OR): 1.04, 95% confidence interval (CI): 0.93-1.16 and OR: 0.97, 95% CI: 0.87-1.09 respectively), a significant association was observed for rs1801278 (OR: 1.34, 95% CI: 1.08-1.66). When meta-analyzed with previous published data, an allelic OR of 1.41 (1.15-1.72; P=0.001) was obtained, so that homozygous R972R individuals have >80% higher risk of failing to OADs as compared with their G972G counterparts. In all, though further studies are needed for confirming this finding, our present data point to IRS1 rs1801278 as a potential biomarker for pursuing the goal of stratified medicine in the field of antihyperglycemic treatment in T2D.