BACKGROUND: Recent evidence suggests that one of the modes of action of metformin may be through phosphorylation of the insulin receptor and insulin receptor substrates. With this in mind, we supposed that the G972A variant of insulin receptor substrate-1 (IRS-1) may modulate the response to metformin treatment in women with polycystic ovary syndrome (PCOS). METHODS: This preliminary study involved 60 randomly selected women with PCOS. All patients received dietary instructions and metformin 500mg three times daily for 6 months. Main outcome measures were androgen levels, parameters of glucose and insulin metabolism and anthropometric variables. After a second evaluation of the patients at 6 months, they were genotyped for the Gly972Arg variant of the IRS-1 gene. RESULTS: Metformin had differential effects on fasting insulin levels, insulin resistance as demonstrated by homeostasis model assessment (HOMA), LH, total testosterone, dehydroepiandrosterone sulphate and free testosterone index on the basis of IRS genotype. The response to metformin therapy in other parameters was not different according to IRS genotype. CONCLUSION: There was a differential effect of metformin therapy in PCOS women on the basis of IRS genotype. This study may call attention to the importance of molecular markers in the management of women with PCOS.