Reduced size at birth has been proposed to be a risk factor for insulin resistance and type 2 diabetes. It is, however, not known whether this association is explained by unfavorable intrauterine environment or by specific susceptibility genotypes predisposing for both reduced fetal growth and insulin resistance and type 2 diabetes. The present study was performed to evaluate whether previously identified amino acid polymorphisms of genes that from animal models have been suggested to play important roles during fetal development are associated with alterations in size at birth. The study population comprised 380 subjects randomly recruited from a population of young Danish Caucasian individuals, aged 18-32 yr. The original data of birth length and weight for 331 of 380 subjects were obtained from the midwife records. The Gly/Arg972 of insulin receptor substrate-1 (IRS-1), the Thr/Ile130 of the hepatocyte nuclear factor-4alpha (HNF-4alpha), the Pro/Ala75 of HNF-6, and the Ile/Leu27, Ala/Val93, and Ser/Asn4s7 polymorphisms of the HNF-lalpha gene were examined for association with birth weight and length and the ponderal index. Using a generalized linear model, including gender and the genotype as fixed variables, and applying Bonferroni correction for multiple testing, we could not demonstrate any significant differences in these estimates among wild-type, heterozygous, and homozygous carriers with respect to any of the gene variants. In conclusion, common variability in the genes encoding the IRS-1, HNF-lalpha, HNF-4alpha, and HNF-6 proteins can be excluded as major factors influencing size at birth among Danish Caucasian subjects.