Aim: The therapeutic efficacy of oral hypoglycaemic drugs varies between individuals, and pharmacogenetic factors contribute to this variability. The Gly972Arg polymorphism in the insulin receptor substrate‐1 (IRS‐1) has been shown to play a role in insulin signal transduction and therapeutic failure to sulphonylurea drugs. Methods: We studied the association between the IRS‐1 polymorphism and the haemoglobin A1c (HbA1c) level in diabetic patients treated with insulinotropic versus non‐insulinotropic hypoglycaemic drugs as a marker for the efficacy of an antidiabetic treatment. Genotyping of the IRS‐1 Arg 972 variant was performed in type 2 diabetes patients treated with either sulphonylurea drugs, glinides or insulin or with metformin, acarbose or glitazones using the polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) method. Results: Significantly higher HbA1c levels were observed in carriers of the Arg 972 variant after treatment with insulinotropic drugs compared to wild‐type carriers (8.3 vs. 7.6%, p = 0.005, independent t ‐test). Furthermore, patients with secondary failure to insulinotropic hypoglycaemic drugs switching finally to insulin showed even higher HbA1c levels in carriers of Arg 972 compared to wild‐type (8.7 vs. 7.6%, p = 0.005, independent t ‐test). Conclusions: Thus, we were able to replicate the earlier findings of an association between the IRS‐1 Arg 972 variant and secondary failure to sulphonylurea drugs, and further observed a general association between HbA1c and this polymorphism in type 2 diabetes patients treated with insulinotropic hypoglycaemic drugs but not with metformin.