Insulin resistance is common in women with PCOS. Insulin and IGF-1 affect glucose uptake and metabolism via insulin receptor substrate (IRS-1) and the phosphotidyl inositol-3-kinase (PI3K) pathway. Impaired glucose metabolism has been observed in granulosa-lutein cells from anovulatory (but not ovulatory) women with PCO (Rice et al. 2005). The aim of this study was to analyse IRS-1 protein expression in human preantral follicles in samples of normal and PCO. Immunohistochemistry was performed on 22 samples of human ovary, with local Ethical Committee approval, using a specific anti-IRS-1 antibody. Sections were analysed for expression of IRS-1 protein in normal (n=7) and polycystic ovaries from ovulatory (n=10) or anovulatory (n=5) subjects (total: 1309 preantral follicles). IRS-1 was localised in oocytes, granulosa, theca and stroma of each type of ovary. In oocytes, the proportion of follicles with positive staining for IRS-1 in the oocyte cytoplasm was significantly reduced in primordial and transitional follicles of anovulatory PCO ovaries compared to normal (χ2; primordial P<0.0001, transitional P<0.0001), or ovulatory PCO (χ2; primordial P<0.0001, transitional P<0.0001). There was also a significant reduction in the proportion of follicles in which IRS-1 was found in the nucleus of the oocyte, in sections from anovulatory PCO compared to normal (χ2; primordial P<0.0001, transitional P<0.0001) or ovulatory PCO (χ2; primordial P<0.0001, transitional P<0.0001). However, as described in a previous report (Yen et al. 2004), we found no differences between types of ovary in distribution of IRS-1 protein in granulosa cells. A functional insulin signalling pathway has been characterised in mouse oocytes and a role in oocyte maturation has been suggested (Avecedo et al. 2007). The reduction of IRS-1 protein is consistent with our previous observations of pathway-specific insulin resistance in PCOS and may have an impact on maturational competence of the oocyte.